Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer

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One of the reasons for this is resistance to chemotherapy. Melatonin and cisplatin may be involved in the chemotherapy resistance of ovarian cancer. Methods A laboratory experiment was performed using melatonin and cisplatin in the SKOV3 cell, from September 2020 to November 2021 at the SCTE and Integrated Laboratory & Research Center Universitas Indonesia. Several variables were used, such as doxorubicin, melatonin, cisplatin, and combination of cisplatin and melatonin at several concentrations (1×, 3/4×, 1/2×, and 1/4×). A total of 24 samples were included and divided into 8 groups. The IC50 values of melatonin, doxorubicin, and cisplatin as well as cell viability was calculated via MTS assay. Subsequently, flow cytometry was performed to assess the effect of cisplatin and melatonin on the mechanisms of CTR1, p-glycoprotein, GSH, ERCC1, e-cadherin, and apoptosis. Analysis of variance and Bonferroni test were employed for the study. Results The IC50 values of melatonin, cisplatin, and doxorubicin were 1.841 mM, 117.5 mM, and 14.72 mM, respectively. The combination groups of cisplatin and melatonin reduced cell viability; decreased the CTR1 mean (19.73), Pgp (6.7), GSH (11.73), and ERCC1 (4.27) in the combination 1 (C1) group; and increased e-cadherin (32.2) and annexin V (53.57) also in the combination 1 (C1) group. Conclusions The combination of melatonin and cisplatin might have an impact on drug resistance via several mechanisms in ovarian cancer. 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F1000Research 2025, 12 :313 ( https://doi.org/10.12688/f1000research.130172.4 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Revised Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] Cut Adeya Adella https://orcid.org/0000-0002-6981-6441 1 , M Fidel Ganis Siregar https://orcid.org/0000-0002-2702-4091 2 , Imam B Putra 3 , [...] Poppy Anjelisa Hasibuan 4 , Andrijono Andrijono 5 , Adang Bachtiar 6 , Sarma N Lumbanraja 7 , Iqbal P Nasution 8 Cut Adeya Adella https://orcid.org/0000-0002-6981-6441 1 , M Fidel Ganis Siregar https://orcid.org/0000-0002-2702-4091 2 , [...] Imam B Putra 3 , Poppy Anjelisa Hasibuan 4 , Andrijono Andrijono 5 , Adang Bachtiar 6 , Sarma N Lumbanraja 7 , Iqbal P Nasution 8 PUBLISHED 06 Jun 2025 Author details Author details 1 Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, Sumatera Utara, 20155, Indonesia 2 Obstetric and Gynecology Department, Fertility Endocrinology Reproduction Division, Medical Faculty, Universitas Sumatera Utara, Medan, Sumatera Utara, 20155, Indonesia 3 Dermatology and Venerology Department, Medical Faculty, Universitas Sumatera Utara, Medan, Sumatera Utara, 20155, Indonesia 4 Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Sumatera Utara, 20155, Indonesia 5 Obstetric and Gynecology Department, Gynecology Oncology Division, Universitas Indonesia, Jakarta, DKI Jakarta, 10430, Indonesia 6 Public Health Faculty, Universitas Indonesia, Jakarta, DKI Jakarta, 10430, Indonesia 7 Obstetric and Gynecology Department, Feto Maternal Division, Medical Faculty, Universitas Sumatera Utara, Medan, Sumatera Utara, 20155, Indonesia 8 Surgery Department, Medical Faculty, Universitas Sumatera Utara, Medan, Sumatera Utara, 20155, Indonesia Cut Adeya Adella Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Resources, Supervision, Writing – Original Draft Preparation M Fidel Ganis Siregar Roles: Formal Analysis, Supervision, Validation, Visualization, Writing – Review & Editing Imam B Putra Roles: Formal Analysis, Project Administration, Supervision, Validation, Writing – Review & Editing Poppy Anjelisa Hasibuan Roles: Formal Analysis, Resources, Supervision, Visualization, Writing – Review & Editing Andrijono Andrijono Roles: Conceptualization, Supervision, Validation, Writing – Review & Editing Adang Bachtiar Roles: Formal Analysis, Supervision, Validation, Writing – Review & Editing Sarma N Lumbanraja Roles: Supervision, Visualization, Writing – Review & Editing Iqbal P Nasution Roles: Supervision, Validation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Oncology gateway. Abstract Background Ovarian cancer management has not yet given a satisfactory result, and the recurrence rate is still high. One of the reasons for this is resistance to chemotherapy. Melatonin and cisplatin may be involved in the chemotherapy resistance of ovarian cancer. Methods A laboratory experiment was performed using melatonin and cisplatin in the SKOV3 cell, from September 2020 to November 2021 at the SCTE and Integrated Laboratory & Research Center Universitas Indonesia. Several variables were used, such as doxorubicin, melatonin, cisplatin, and combination of cisplatin and melatonin at several concentrations (1×, 3/4×, 1/2×, and 1/4×). A total of 24 samples were included and divided into 8 groups. The IC50 values of melatonin, doxorubicin, and cisplatin as well as cell viability was calculated via MTS assay. Subsequently, flow cytometry was performed to assess the effect of cisplatin and melatonin on the mechanisms of CTR1, p-glycoprotein, GSH, ERCC1, e-cadherin, and apoptosis. Analysis of variance and Bonferroni test were employed for the study. Results The IC50 values of melatonin, cisplatin, and doxorubicin were 1.841 mM, 117.5 mM, and 14.72 mM, respectively. The combination groups of cisplatin and melatonin reduced cell viability; decreased the CTR1 mean (19.73), Pgp (6.7), GSH (11.73), and ERCC1 (4.27) in the combination 1 (C1) group; and increased e-cadherin (32.2) and annexin V (53.57) also in the combination 1 (C1) group. Conclusions The combination of melatonin and cisplatin might have an impact on drug resistance via several mechanisms in ovarian cancer. READ ALL READ LESS Keywords Cisplatin, melatonin, doxorubicin, SKOV3 Corresponding Author(s) Cut Adeya Adella ( [email protected] ) Close Corresponding author: Cut Adeya Adella Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Adeya Adella C et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Adeya Adella C, Siregar MFG, Putra IB et al. Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.12688/f1000research.130172.4 ) First published: 21 Mar 2023, 12 :313 ( https://doi.org/10.12688/f1000research.130172.1 ) Latest published: 06 Jun 2025, 12 :313 ( https://doi.org/10.12688/f1000research.130172.4 ) Revised Amendments from Version 3 There are several new addition in the mechanism of melatonin in other cancer that have been added to discussion. Also this study was performed only in one cell line, to show several pathway of melatonin, there should be other study that performed on several cell line, so we have been added the limitation section. There are several new addition in the mechanism of melatonin in other cancer that have been added to discussion. Also this study was performed only in one cell line, to show several pathway of melatonin, there should be other study that performed on several cell line, so we have been added the limitation section. See the authors' detailed response to the review by Tharcisio C. Tortelli See the authors' detailed response to the review by Pavel Souček See the authors' detailed response to the review by Seyed Mostafa Mir READ REVIEWER RESPONSES Introduction To date, the management of ovarian cancer, especially epithelial ovarian cancer, has not yet given satisfactory results ( Razi et al. , 2016 ). Ovarian cancer is known to have high morbidity and mortality rates as well as poor prognosis ( Coburn et al. , 2017 ). It ranks third in the world after cervical and uterine cancer ( Bray et al. , 2018 ). According to the Global Burden Cancer 2020 database, the number of ovarian cancer cases worldwide is 313,959, with the number of deaths being 207,252 ( Sung et al. , 2021 ). In Indonesia, the rate of ovarian cancer is still high at around 3,398 from 2016 to 2020 ( INASGO, 2021 ). At present, ovarian cancer recurrence rate is still high and influences the morbidity and mortality rates. One of the reasons why the recurrence rate remains high is chemotherapy resistance, especially by cisplatin at cancer stem cell (CSC), because evasion from apoptosis caused the cell to redevelop after therapy has been performed ( Woo et al. , 2012 ). There are multiple factors in cisplatin resistance, and the mechanism is still unclear from the perspective of cellular mechanism ( Sousa et al., 2014 ). There are many intracellular mechanisms that affect the evasion of a cell from the cytotoxic effect of chemotherapy, such as the process that regulates drug bioavailability, mesenchymal epithelial transition, and oncogenic signals producing a phenotype that causes resistance to chemotherapy ( Yeldag et al., 2018 ). Melatonin has been considered an alternative for managing chemotherapy resistance, especially in ovarian cancer ( Chuffa et al., 2017 ). It is synthesized at the pineal gland. Melatonin exerts antioxidant and antiapoptotic effects on normal cells but exerts pro-oxidative, antiproliferative, antiangiogenic, and immunomodulatory effects on cancer cells, especially hormone-dependent cancer ( Su et al. , 2017 ). Melatonin has been known for it’s oncostatic acitivity in several malignancies. Melatonin has anticancer and oncostatic effects, e.g., it potentiates antimetastasis, induces anticancer immunity, modulation of cell cycle, induces autophagy, modulate oncogene expression, enhances drug sensitivity, induces apoptosis, inhibits cancer growth, and exhibits antiangiogenic and antiinvasive activities ( Su et al., 2017 ; Targhazeh et al. , 2022 ). In addition, melatonin has a good effect on clinical outcomes in several cancers such as colon, breast, lung, and ovarian cancers ( Li et al. , 2017 ). However, to date, the study of melatonin in cisplatin-resistant cancer is scarce. Therefore, this study was conducted to find new alternatives for ovarian resistant cancer cell by using a combination of cisplatin and melatonin. Methods Materials and sample size In this study, a laboratory experiment on the combination of cisplatin and melatonin in cisplatin-resistant ovarian cancer cell was conducted using SKOV3 obtained from the American Type Culture Collection (no. HTB-77). This research was conducted at the SCTE (Stem Cell and Tissues Engineering Research Cluster) at the Medical Faculty of Universitas Indonesia. Furthermore, flow cytometry (BD FACS ARIA III) was performed at the Integrated Laboratory of the Faculty of Medicine, Universitas Indonesia, from September 2020 to November 2021. This research has been approved by the ethics committee of Universitas Indonesia with 419/UN2.F1/ETIK/PPM.00.02/2021 on May, 3 rd 2021. The materials used were IC50 melatonin [Liftmode], IC50 doxorubicin [MBS], IC50 cisplatin [Mybiosource], sodium bicarbonate [Sigma-aldrich], aquabidest, microcarrier beads [Sigma-aldrich], trypsin-EDTA [Gibco], phospate buffer saline (PBS) [Gibco], dimethyl sulfoxide (DMSO) [Gibco], Roswel Park Memorial Institute [RPMI] medium, antibiotic [Penstrep], antimycotic [Gibco], tryphan blue [Gibco], heparin [Gibco], fetal bovine serum (FBS) [Amresco], ethanol 70%, aquadest, whitening [Bayclin], Tris-Cl 0,5 M pH 6,8 [Invitrogen], and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) [Promega]. This research used 8 groups of samples. Mead’s formula was used to calculate sample size. Minimum samples were 16 with three times repetition in each group, so the total was 24 samples. The samples were described in Table 1 and for the protocols can be accessed from dx.doi.org/10.17504/protocols.io.yxmvm2539g3p/v1 . Table 1. Sample size in each group. Study groups Well Size Cell Control 3 IC50 Doxorubicin 3 IC50 Melatonin 3 IC50 Cisplatin 3 Group 1 1 x IC50 (Melatonin-Cisplatin) 3 Group 2 ¾ x IC50 (Melatonin-Cisplatin) 3 Group 3 ½ x IC50 (Melatonin-Cisplatin) 3 Group 4 ¼ x IC50 (Melatonin-Cisplatin) 3 TOTAL 24 The groupings were as follows: cell control (without any treatment), IC50 doxorubicin, IC50 melatonin, IC50 cisplatin, C1 (combination of 1× IC50 cisplatin and 1x melatonin), C2 (combination of ¾× IC50 cisplatin and ¾× melatonin), C3 (combination of ½× IC50 cisplatin and ½× melatonin), and C4 (combination of ¼× IC50 cisplatin and ¼× melatonin). The dependent variables were the morphology of SKOV3 cells visualized using a microscope with 100x magnification, percentage of cancer cell viability determined via MTS assay, and cell percentage that expressed CTR-1 (as an influx marker) [MBS], p-glycoprotein (Pgp) (as an efflux marker) [FITC], gamma-glutamylcysteinylglycine (GSH) (as a drug inactivation marker) [GSH Kit], excision repair cross-complementation 1 (ERCC 1) (as a damage repair marker) [PE 647], e-cadherin (as a mesenchymal epithelial transition marker) [FITC], and apoptosis (as an annexin V marker) [Mybiosource] using flow cytometry. Positive control was performed with doxorubicin. SKOV 3 cell culture Treated cells were harvested by adding 1 mL tripsin-EDTA, centrifuged at 2000 rpm for 5 minutes. The fifth passage of the SKOV3 cell was obtained from a cryopreservation tank and thawed at 37°C for 2 min. Then, the cell was centrifuged for 10 min, and the supernatant was discharged; 1–2 mL of the complete medium was added for cell counting. The cells were cultured and harvested, 2–3 mL of trypsin was added and incubated for 5 min, then the suspension was centrifuged for 10 min and then re-harvested from the 96-well plate for the MTS assay [Promega]. IC50 Determination IC50 was used to express the 50% decrease in cell viability. To determine the IC50, each concentration of solutions was tested in each cell. The IC50 values of melatonin, cisplatin, and doxorubicin were assessed. Different concentrations were tested to find the IC50 of each variable as follows: melatonin (0.1, 0.5, 1, 2, 5 mM), doxorubicin (25, 50, 100, 150, 200, 300 μM), and cisplatin (10, 20, 40, 50, 80, 100, 200 μM). Spectrophotometry [Shimadzu] was employed with λ = 490 nm for the absorbency. Graphpad software was used to analyze the IC50 values. The IC50 values of the materials were 1.841 mM for melatonin, 117.5 μM for cisplatin, and 14.72 μM for doxorubicin. Cytotoxic activity Cells were treated using Roswell Park Memorial Institute (RPMI) medium consisting of 1% penicillin-streptomycine [Penstrep], 1% fungizone [Gibsco], 10% fetal bovine serum [Amresco], and ethanol 70% in a flask incubated at 37°C with CO 2 5%. SKOV3 cells were seeded onto the 96-well plate with 25x10 4 cell/well density, then incubated at 37°C for 24 h, then each cell was exposed to each material and incubated for 48 h. To measure the cell viability percentage and cytotoxic activity, MTS assay was employed. The principle is formazan crystal will be produced by the viable cell much more than the nonviable cell. Each of the materials were exposed to the cells and MTS solution was added at each of the wells, then read in λ = 490 nm. Preparation of cell for flow cytometry Flow cytometry was performed by adding EDTA into the plate and then centrifuging several times, and cell pellets were washed once with PBS. The cell was put into flow cytometry tube and added 1 mL stain buffer solution, then centrifuged at 2100 rpm for 5 minutes. The supernatant was then separated and the sediment was collected. Flow cytometry of CTR-1 and Pgp P-glycoprotein antibody was added into the sediment and incubated for 15 minutes at room temperature, washed with buffer stain, ad centrifuged at 2100 rpm for 5 minutes. 1 mL cytofix was then added and incubated at room temperature for 10 minutes. The cell was centrifuged at 2100 rpm for 5 minutes, the supernatant was discharged and washed with 1 mL of permwash buffer, then recentrifuged at 2100 rpm for 5 minutes. The supernatant was separated, CTR-1 antibody was added, and it was incubated for 20 minutes at room temperature, then washed with permwash buffer and recentrifuged at 2100 rpm for 5 minutes. Samples were analyzed with flow cytometry (BD FACS ARIA III). Flowcytometry of GSH 5 μL of GSH antibody was added into the sample, which was then incubated at 37°C for 30 minutes, washed with 1 mL buffer, and centrifuged at 2100 rpm for 5 minutes. The sediment was dissolved with stain buffer. Samples were analyzed using flow cytometry (BD FACS ARIA III). Flowcytometry of ERCC-1 and E-Cadherin Antibodies of ERCC and E-Cadherin were added into the sample, incubated at room temperature for 20 minutes, then washed with 1 mL permwash buffer for 5 minutes and centrifuged at 2100 rpm for 5 minutes. The sediment was collected and dissolved with stain buffer. Samples were analyzed using flow cytometry (BD FACS ARIA III). Flowcytometry of apoptosis 0.1 mL annexin V reagent was added into the sediment, incubated at room temperature for 20 minutes, washed with 1 mL stain buffer and recentrifuged at 2100 rpm for 5 minutes. The sediment was collected and stain buffer was added. Samples were analyzed using flowcytometry (BD FACS ARIA III). Statistical analysis Mean ± SD was used to express the data. ANOVA with post hoc Bonferroni test was employed for statistical analysis, with significant differences determined as p <0.05. All the statistics were analyzed using SPSS 21. Results In this study, SKOV3 cells were used. SKOV3 cell culture was observed under a microscope, as presented in Figure 1 . After calculating the IC50 values of the materials (melatonin, 1.841 mM; cisplatin, 117.5 μM; and doxorubicin, 14.72 μM), cell viability was calculated via MTS assay and observed under microscope as in Figure 2 . The highest rate of cell viability decrease was in group C1 (IC50 melatonin and cisplatin) at 37.57%, as shown in Table 2 ( Adella, 2023a , 2023b , 2023c ). Figure 1. SKOV 3 cell culture under microscope with 100× magnification. Figure 2. Microscopic feature of SKOV3 after exposure of MTS for 48 hours with magnification 100×. Table 2. Viability cell study. Study groups Percentage of viability cell Cell control 100% Medium control 0% IC50 Doxorubicin 38.31% IC50 Melatonin 47.68% IC50 Cisplatin 55.16% Group 1 (1x IC50 Melatonin + IC50 Cisplatin) 37.57% Group 2 (3/4x IC50 Melatonin + IC50 Cisplatin) 40.63% Group 3 (1/2x IC50 Melatonin + IC50 Cisplatin) 42.78% Group 4 (1/4x IC50 Melatonin + IC50 Cisplatin) 48.43% Influx mechanism using CTR1 CTR1 is a marker of drug influx. An increase in CTR1 expression indicates an increase of drug influx into the cell, which suggests decreased cancer cell resistance to chemotherapy. As can be seen from Table 3 and Figure 3 , the control group has the lowest mean expression among the groups. On the contrary, the doxorubicin group has the highest CTR1 expression, indicating that doxorubicin has a higher influx rate than other groups. However, among the combination groups, C1 and C2 had the highest CTR1 expression ( P < 0,001), suggesting that these groups have the highest influx rate among the experimental groups. The IC50 melatonin group had lower CTR1 expression than groups C1 and C2, which shows that chemotherapy influx was better in C1 and C2 than the melatonin-only group. If compared with the IC50 of cisplatin, all the combination groups show that the CTR1 expression was higher than the cisplatin alone, which indicated that the combination of cisplatin and melatonin groups were better to increase the influx of the drug than the cisplatin-only group. Table 3. CTR 1 expression in study groups. Groups Mean (SD) p a Posthoc b Dox Mel Cis C1 C2 C3 C4 Control 2.17 (0.21) <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 IC50 Doxorubicin 30.33 (0.4) <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 IC50 Melatonin 14.8 (0.1) <0.001 <0.001 <0.001 1.000 0.001 IC50 Cisplatin 7.37 (0.7) <0.001 <0.001 <0.001 <0.001 C1 19.73 (0.49) 1.000 <0.001 <0.001 C2 18.73 (0.84) <0.001 <0.001 C3 14.53 (1.14) 0.002 C4 11.77 (0.55) a ANOVA. b Bonferroni. Figure 3. CTR 1 expression percentage. Efflux mechanism using P-glycoprotein (Pgp) Pgp is an efflux membrane transporter of toxins, cell endogen metabolites, and chemotherapy especially in resistance cells. A high percentage of Pgp indicates a high ability of the cell to inhibit a cytotoxic response, suggesting high chemotherapy resistance of cancer cells. As can be seen from Table 4 and Figure 4 , the control group has the highest Pgp expression (44.37%). Among the combination groups, from the mean expression, C1 group has the lowest Pgp expression (6.7%) of all combination groups and C4 has the highest Pgp expression (20.87%). This result indicates that group C1 had the ability to decrease Pgp expression more than the cisplatin-only group (16%). From pair of IC50 melatonin and C1 group, it was shown no difference statistically, but from other pairs shown significantly difference in posthoc analysis. A low rate of drug efflux activity indicates decreased chemotherapy resistance and better outcome. The combination groups had better ability to decrease the efflux mechanism than the cisplatin-only group. Table 4. Pgp expression in study groups. Groups Mean (SD) p a Posthoc b Dox Mel Cis C1 C2 C3 C4 Control 44.37 (1.55) <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 IC50 Doxorubicin 0 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 IC50 Melatonin 7.37 (0.21) <0.001 1.000 0.986 <0.001 <0.001 IC50 Cisplatin 16 (1.59) <0.001 <0.001 1.000 <0.001 C1 6.7 (0.17) 0.161 <0.001 <0.001 C2 9.1 (0.1) <0.001 <0.001 C3 15.43 (1.25) <0.001 C4 20.87 (0.49) a ANOVA. b Bonferroni. Figure 4. P glycoprotein expression percentage. Drug inactivation mechanism using GSH GSH is a peptide, which involved in drug inactivation protein marker. As can be seen from Table 5 and Figure 5 , the control group has the highest GSH peptide level (45.23%), whereas the positive control group has the lowest (1.33%), indicating that without giving the materials, the GSH level would high. But if doxorubicin is given, the GSH level would be lowered. Among the combination groups, group C1 has the lowest GSH level (11.73%). When compared with the melatonin-only group (12.57%), group C1 had a lower GSH level. On the other hand, when compared with the cisplatin-only group, all of the combination groups had a higher ability to decrease the GSH level than the cisplatin-only group. But, from pair of IC50 melatonin and C1 in the post hoc analysis, shown no difference statistically. This suggested that the combination groups had decreased drug inactivation activity and chemotherapy resistance as well as a better outcome than the cisplatin-only group. This is presented in Table 5 . Table 5. GSH level in study groups. Groups Mean (SD) p a Posthoc b Dox Mel Cis C1 C2 C3 C4 Control 45.23 (0.5) <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 IC50 Doxorubicin 1.33 (0.06) <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 IC50 Melatonin 12.57 (0.12) <0.001 1.000 <0.001 <0.001 <0.001 IC50 Cisplatin 33.2 (0.87) <0.001 <0.001 <0.001 <0.001 C1 11.73 (0.67) <0.001 <0.001 <0.001 C2 20.5 (1.42) 0.008 <0.001 C3 23.07 (0.23) <0.001 C4 28.93 (0.38) a ANOVA. b Bonferroni. Figure 5. GSH level percentage. Excision repair cross-complementation 1 (ERCC1) mechanism ERCC1 is a transcription factor used as a DNA repair marker. A high ERCC1 expression indicates high DNA repair mechanism in cancer cells. As can be seen from Table 6 and Figure 6 , the control group has the highest ERCC1 expression (48.07%), whereas the positive control group has the lowest (1.57%). Among the combination groups, groups C1, C2, and C3 have the ability to decrease the ERCC1 expression more than the melatonin-only and cisplatin-only groups, but C1 group had the highest ability. The lower the DNA repair activity, the more the chemotherapy resistance decreases, which is shown in combination of melatonin and cisplatin groups. Table 6. ERCC1 expression in study groups. Groups Mean (SD) p a Posthoc b Dox Mel Cis C1 C2 C3 C4 Control 48.07 (0.45) <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 IC50 Doxorubicin 1.57 (0.06) <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 IC50 Melatonin 14.63 (0.49) <0.001 <0.001 <0.001 <0.001 <0.001 IC50 Cisplatin 20.2 (0.17) <0.001 <0.001 <0.001 0.001 C1 4.27 (0.21) <0.001 <0.001 <0.001 C2 9.53 (0.6) 0.001 <0.001 C3 11.63 (0.6) <0.001 C4 22.8 (0.52) a ANOVA. b Bonferroni. Figure 6. ERCC1 expression percentage. E-cadherin examination E-cadherin is a marker of epithelial mesenchymal transition. A high e-cadherin expression indicates low epithelial mesenchymal transition, which has a low impact on tumor invasion and drug resistance. As can be seen from Table 7 and Figure 7 , the positive control group has the highest e-cadherin expression (64.2%), whereas the control group has the lowest (1.7%). When compared with the cisplatin-only group, the combination groups C1-C3 had higher e-cadherin expression than the cisplatin-only group. This suggested that the combination of melatonin and cisplatin might decrease epithelial mesenchymal transition (increased expression of e-cadherin) more than the cisplatin-only group; a decrease in drug resistance could also be observed. Table 7. E-Cadherin expression in study groups. Groups E_Chaderin p-value a P-value b Mean ± SD Control IC50 Doxorubicin IC50 Melatonin IC50 Cisplatin C1 C2 C3 C4 Control 1.70 ± 0.10 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 IC50 Doxorubicin 64.2 ± 1.76 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 IC50 Melatonin 19.2 ± 0.36 <0.001 <0.001 <0.001 <0.001 <0.001 IC50 Cisplatin 7.20 ± 0.59 <0.001 <0.001 <0.001 1.00 C1 32.2 ± 1.60 <0.001 <0.001 <0.001 C2 15.53 ± 0.85 0.588 <0.001 C3 14.30 ± 0.46 <0.001 C4 6.93 ± 0.65 a ANOVA. b Bonferroni. Figure 7. E-Cadherin expression percentage. Apoptosis mechanism using annexin V Annexin V was used as an apoptosis marker in this research. A high annexin V activity indicates high apoptosis activity. As can be seen from Table 8 and Figure 8 , the positive control group has the highest annexin V activity (70.9%), whereas the control group has the lowest (1.2%). Among the combination groups, group 1 has the highest annexin V activity (53.57%). Compared with the melatonin-only group, all combination groups had a higher ability to decrease annexin V expression. Additionally, compared with the cisplatin-only group, the combination groups all had a better ability to increase apoptosis than the cisplatin-only group. This suggested that the combination of melatonin and cisplatin increases apoptosis to reduce the drug resistance mechanism. Table 8. Annexin V expression in study groups. Groups Mean (SD) p a Posthoc b Dox Mel Cis C1 C2 C3 C4 Control 1.2 (0) <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 IC50 Doxorubicin 70.9 (0.1) <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 IC50 Melatonin 15.77 (0.21) 0.005 <0.001 <0.001 <0.001 <0.001 IC50 Cisplatin 10.87 (0.91) <0.001 <0.001 <0.001 <0.001 C1 53.57 (1.33) <0.001 <0.001 <0.001 C2 46.77 (0.06) <0.001 <0.001 C3 32.43 (2.83) <0.001 C4 23.2 (1.31) a ANOVA. b Bonferroni. Figure 8. Annexin V expression percentage. Discussion The IC50 of doxorubicin was used as a positive control in this study as doxorubicin has much evidence as an anticancer agent and has been demonstrated to be effective when cells are resistant to cisplatin ( Yi S et al., 2020 ). Doxorubicin has a DNA intercalation chain mechanism, inhibition of topoisomerase II to destroy DNA and increase apoptosis ( Johnson and Dubey, 2021 ). The combination groups had higher cell viability decrease than the cisplatin group. These groups may have the capability to increase the cytotoxic effect of chemotherapy more than that of the single-use therapy. Melatonin exhibits anti-inflammatory, anti-tumor, and anti-proliferative activities, with minimal side effects. In addition as oncostatic agent, it was found to reduce cell proliferation, metastasis, angiogenesis and act as a pro-apoptosis and immunomodulator agent in ovarian cancer. Melatonin exhibits anti-inflammatory, anti-tumor, and anti-proliferative activities, with minimal side effects. In addition as oncostatic agent, it was found to reduce cell proliferation, metastasis, angiogenesis and act as a pro-apoptosis and immunomodulator agent in ovarian cancer. Melatonin reduces p52 and p65 binding activity by downregulate MMP-9, regulates cell motility and activation of MMP-9 by Akt-mediated JNK1/2 and ERK1/2 pathways, this is shown in metastasis activity. Melatonin acts as pro-apoptosis and tumor growth inhibitor by downregulation of MDM2 (E3 ubiquitin ligase), that promotes acetylation of p53 acetylation which lead to cell cycle arrest by elevating p21 levels. Melatonin also inactivates Akt, reduces apoptosis resistance of tumor cells, lowers Snail and vimentin levels and enhances e-cadherin activity. Melatonin decreases ROS and inactivates HIF-α and VEGF (Vascular Endothelial Growth Factor) in malignancy ( Chuffa et al. , 2017 ; Heydari et al., 2023 ). Melatonin has no issues regarding bioavailability compared with other drugs because it has faster solubility through the cell and nuclear membranes ( Tamura et al., 2020 ). CTR1 and Pgp were found to be associated with cell resistance. Low influx and high efflux may contribute to drug resistance ( Zhang et al., 2019 ). CTR1 plays a role in the absorption of platinum drugs, such as cisplatin and oxaliplatin, and decreases transporter expression, thus influencing tumor resistance ( Chen and Chang , 2019 ). Pgp may pump the drug outside of the cell to reduce cytotoxic activity. A high Pgp indicates a high ability of the cell to inhibit the cytotoxic agent ( Amiri-Kordestani et al., 2012 ). Melatonin is capable of reducing Pgp in diffuse large B-cell lymphoma and activating the NF-kB pathway. In a study using the combination of epirubicin and melatonin, melatonin made the lymphoma cell sensitive to epirubicin from the inhibition of Pgp expression through the pathway of NF-kB. Melatonin decreases P65 in the nucleus and inhibits Pgp expression ( Liu et al., 2021 ). In colorectal cancer that resist to oxaliplatin (using LS174T/DR cell line), combination of melatonin and oxaliplatin reduce oxaliplatin resistance by lowering Pgp activities in LS174T/DR and also suppress colorectal proliferation ( Dehghanzad et al., 2024 ). GSH has the ability to detoxify intracellular toxins, but the GSH in cell cancer is capable of inhibiting and inactivating chemotherapy ( Tapia et al., 2013 ). GSH binds to cisplatin to inhibit cisplatin binding with DNA, reduce reactive oxygen species, and decrease cell sensitivity to apoptosis ( Galluzzi et al., 2012 ). Melatonin can decrease the GSH level and increase the GSH peroxidase activity ( Medina-Leendertz et al., 2018 ). Furthermore, it induces antioxidant synthesis by inducing gamma glutamylcysteine synthetase ( Meng et al., 2017 ). In addition, melatonin increases antioxidant activity that increases glutathione level and induces glutathione peroxidase ( Harderland, 2017 ). Melatonin increases the apoptosis activity of cisplatin, reduces oxidative stress by decreasing the GSH level, and increases glutathione synthesis ( Fernandez et al., 2019 ). Melatonin has the ability to inhibit mTOR and ERCC1 expressions and increase the activity of intracellular autophagosomes. It is used as a cancer therapy adjuvant to repair the sensitivity of chemotherapy and managing the side effects of cisplatin ( Bennukul et al., 2014 ). Melatonin affects the DNA repair mechanism by increasing ERCC-1 XPF activity, a NER (Nucleotide Excision Repair) that functions as 5’ endonuclease in the repair mechanism pathway ( Mir et al ., 2021 ). Melatonin reduce DNA damage and apoptosis, increase ERCC1 gene which is involved in DNA damage repair in hepatocellular carcinoma (HepG2) cells ( Bennukul et al., 2014 ). ERCC1 overexpression has poor prognosis in patients with osteosarcoma or lung cancer who received cisplatin. Li et al. (2017) demonstrated that low ERCC1 expression increases the sensitivity of platinum chemotherapy in ovarian cancer. The low repair activity of the DNA decreases chemotherapy resistance ( Li et al., 2017 ). E-cadherin has an impact in cell adhesion and influences cell growth. A decrease in e-cadherin expression increases activity of epithelial mesenchymal transition, thus reducing the cell adhesion strength ( Rosso et al., 2017 ). Loss of e-cadherin will activates signalling pathways and transcription factors such as β-catenin ( Su et al., 2017 ). High e-cadherin was associated with low activities of invasive cancer and metastasis ( Loh et al., 2019 ). Melatonin administration increased e-cadherin expression, decreased N-cadherin and vimentin expressions in CSC from CMT-U229. Melatonin may decrease the migration and invasion activities of cancer cells ( Goncalves et al., 2016 ). It also decreases proteins associated with inflammation, oxidative stress, cell-cycle, proliferation, and apoptosis ( Zare et al., 2019 ). In gastric cancer, melatonin upregulate e-cadherin by involving in interference of interaction between C/EBPβ and NF-κB through induction of endoplasmic reticulum stress that activates calpain ( Su et al., 2017 ). Melatonin also increase e-cadherin, reduce MMP-9 expression and inhibit NF-κB pathway in esophageal cancer ( Gu et al., 2020 ). Apoptosis indicates low chemotherapy resistance. In this study, we used annexin V as the marker. High annexin V expression indicates high apoptosis activity in the cell ( Wang et al., 2012 ). Melatonin increases p53 expression and activates it, increasing apoptosis in several cancers such as colon and uterine cancer. Melatonin is involved in the BAX gene expression, decreases the expression of BCL-2 as an antiapoptotic gene, and regulates the Bax/Bcl-2 ratio ( Chuffa et al., 2017 ). In human myeloid leukemia, melatonin also inhibit progression of G1 to S phase by up-regulate Bax and down-regulate Bcl-2 ( Shen et al., 2017 ). Other studies also reported melatonin activity in inducing apoptosis by upregulation of pro-apoptotic (p53, Bax, total and cleaved caspase-3) and anti-apoptotic (Bcl-2 and survivin) also downregulation of cyclin dependent kinase ( Chuffa et al., 2017 ). Melatonin and cisplatin potentiate apoptosis by increasing the depolarization of mitochondrial membrane, activating caspase-3/7, and inducing cell-cycle arrest, if compared with the cisplatin-only group ( Plaimee et al., 2015 ). Limitation This study has shown that cisplatin combine with melatonin may reduce the cisplatin resistance in ovarian cancer, but this study only use one cell line which is SKOV3. In order to see the impact of the combination, study on the several cell lines should be performed. The result of this study may just generally indicative, so another study must be performed and added to see the effect of the melatonin and cisplatin combination in reducing the chemoresistance. The authors also suggest that there should be another research that performed in vivo to see the bioavailability and dose of the combination melatonin and cisplatin, so it can be optimized the cancer treatment. Conclusion This study has shown that combination of melatonin and cisplatin may reduce the chemoresistance in SKOV3 cell line with several pathways such as decreasing cancer cell viability, increased influx activity by increasing CTR-1 expression, reduced efflux activity by reducing Pgp expression, decrease drug inactivity by reducing GSH expression, decrease DNA repair mechanism shown by reduced ERCC-1 expression, decreased epithelial mesenchymal transition by increasing e-cadherin expression, and increase apoptosis mechanism by increase annexin V expression. This study may describe the melatonin effect on chemotherapy resistance. Data availability Underlying data Mendeley: Raw Data of Melatonin-Cisplatin. https://doi.org/10.17632/ybpbjbkfb4.1 ( Adella, 2023a ) Mendeley: Combination of Cisplatin and Melatonin on the Inhibition of Cisplatin Resistance in SKOV3 Cells. https://www.doi.org/10.17632/ftdpsfwrtv.1 ( Adella, 2023b ) Mendeley: File for Combination of Melatonin and Cisplatin on the Inhibition of Ovarian Cancer Cell. https://doi.org/10.17632/475dpkhk3w.2 ( Adella, 2023c ) Adella, Cut Adeya (2023), “Figure of Melatonin and Cisplatin Research”, Mendeley Data, V1, doi: 10.17632/42zjfg2z9d.1 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Acknowledgments All of the authors give regard to the people who participated in this research. References Adella CA: Raw Data of Melatonin-Cisplatin. [Dataset]. Mendeley Data. 2023a; V1 . Publisher Full Text Adella CA: Combination of Cisplatin and Melatonin on the Inhibition of Cisplatin Resistance in SKOV3 Cells. [Dataset]. Mendeley Data. 2023b; V1 . Publisher Full Text Adella CA: Combination of Melatonin and Cisplatin on the Inhibition of Ovarian Cancer Cell. [Dataset]. Mendeley Data. 2023c; V2 . Publisher Full Text Amiri-Kordestani L, Basseville A, Kurdziel K, et al. : Targeting MDR in breast and lung cancer: Discriminating its potential importance from the failure of drug resistance reversal studies. Drug Resist. Updat. 2012; 15 (1–2): 50–61. PubMed Abstract | Publisher Full Text | Free Full Text Bennukul K, Numkliang S, Leardkamolkarn V: Melatonin attenuates cisplatin-induced HepG2 cell death via the regulation of mTOR and ERCC-1 expressions. World J. Hepatol. 2014; 6 (4): 230–242. PubMed Abstract | Publisher Full Text | Free Full Text Bray F, Ferlay J, Soerjomataram I, et al. : Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018; 68 (6): 394–424. PubMed Abstract | Publisher Full Text Chen SH, Chang JY: New Insights into Mechanisms of Cisplatin Resistance: From Tumor Cell to Microenvironment. Int. J. Mol. Sci. 2019; 20 (17). Publisher Full Text Chuffa L, Reiter R, Lupi L: Melatonin as a promising agent to treat ovarian cancer: molecular mechanisms. Carcinogenesis. 2017; 38 (10): 945–952. Publisher Full Text Coburn S, Bray F, Sherman M, et al. : International patterns and trends in ovarian cancer incidence, overall and by histologic subtype. Int. J. Cancer. 2017; 140 (11): 2451–2460. PubMed Abstract | Publisher Full Text | Free Full Text Dehghanzad M, Mohammadi M, Nejati M, et al. : The potential effect of melatonin in oxaliplatin combination therapy against chemoresistant colorectal cancer. Mol. Biol. Rep. 2024; 51 : 348. Publisher Full Text Fernandez-Gil BI, Guerra-Librero A, Shen YQ, et al. : Melatonin enhances cisplatin and radiation cytotoxicity in head and neck squamous cell carcinoma by stimulating mitochondrial ROS generation, apoptosis, and autophagy. Oxidative Med. Cell. Longev. 2019; 2019 : 1–12. PubMed Abstract | Publisher Full Text | Free Full Text Galluzzi L, Senovilla L, Vitale I, et al. : Molecular mechanisms of cisplatin resistance. Oncogene. 2012; 31 (15): 1869–1883. Publisher Full Text Goncalves N, Colombo J, Lopes JR, et al. : Effect of Melatonin in Epithelial Mesenchymal Transition Markers and Invasive Properties of Breast Cancer Stem Cells of Canine and Human Cell Lines. PLoS One. 2016; 11 (3): e0150407. PubMed Abstract | Publisher Full Text | Free Full Text Gu H, Shen Q, Mei D, et al. : Melatonin inhibit TE-1 esophageal cancer cells metastasis by supressing the NF-κB signalling pathway and decreasing MMP-9. Ann. Clin. Lab. Sci. 2020; 50 : 60–72. Harderland R: Melatonin and the electron transport chain. Cell. Mol. Life Sci. 2017; 74 (21): 3883–3896. Publisher Full Text Heydari N, Memar MY, Reiter RJ, et al. : Melatonin: An anticancer molecule in esophageal squaous cell carcinoma: a mechanistic review. Melatonin Res. 2023; 6 (1): 59–71. Publisher Full Text Indonesia Society of Gynecologic Oncology (INASGO), 2021: National data, 2000-2016. Reference Source Johnson K, Dubey R: Doxorubicin. StatPearls; 2021. Li Y, Li S, Zhou Y, et al. : Melatonin for the prevention and treatment of cancer. Oncotarget. 2017; 8 (24): 39896–39921. PubMed Abstract | Publisher Full Text | Free Full Text Li C, Zhu X, Chen S, et al. : Melatonin promotes the proliferation of GC-1 spg cells by inducing metallothionein-2 expression through ERK1/2 signaling pathway activation. Oncotarget. 2017; 8 (39): 65627–65641. PubMed Abstract | Publisher Full Text | Free Full Text Liu K, Song J, Yan T, et al. : Melatonin increases the chemosensitivity of diffuse large B-cell lymphoma cells to epirubicin by inhibiting P-glycoprotein expression via the NF-κB pathway. Transl. Oncol. 2021; 14 (1): 100876. PubMed Abstract | Publisher Full Text | Free Full Text Loh CY, Chai JY, Tang TF, et al. : The E-cadherin and N-cadherin switch in epithelial and mesenchymal transition: signalling, therapeutics implications, and challenges. Cells. 2019; 8 (10): 1118. PubMed Abstract | Publisher Full Text | Free Full Text Medina-Leendertz S, Mora M, Vielma JR, et al. : Melatonin decreases oxidative stress in Drosophila melanogaster exposed to manganese. Investig. Clin. 2018; 59 (3): 230–241. Publisher Full Text Meng X, Li Y, Li S, et al. : Dietary sources and bioactivities of melatonin. Nutrients. 2017; 9 (4): 367. PubMed Abstract | Publisher Full Text | Free Full Text Mir MS, Aliarab A, Goodarzi G, et al. : Melatonin: A smart molecule in the DNA repair system. Cell Biochem. Funct. 2021; 40 : 4–16. Publisher Full Text Plaimee P, Weerapreeyakul N, Barusrux S, et al. : Melatonin potentiates cisplatin-induced apoptosis and cell cycle arrest in human lung adenocarcinoma cells. Cell Prolif. 2015; 48 (1): 67–77. PubMed Abstract | Publisher Full Text | Free Full Text Razi S, Ghoncheh M, Mohammadian-Hafshejani A, et al. : The incidence and mortality of ovarian cancer and their relationship with the Human Development Index in Asia. Ecancer Medical Science. 2016; 10 : 628. Publisher Full Text Rosso M, Majem B, Devis L, et al. : E-cadherin: A determinant molecule associated with ovarian cancer progression, dissemination and aggressiveness. PLoS One. 2017; 12 (9): 1–25. Publisher Full Text Shen YQ, Guerra-Librero A, Fernandez-Gil B, et al. : Combination of melatonin and rapamycin for head and neck cancer therapy: Suppression of AKT/mTOR pathway activation, and activation of mitophagy and apoptosis via mitochondrial function regulation. J. Pineal Res. 2017; 64 . Publisher Full Text Sousa GF, Wlodarczyk S, Monteiro G: Carboplatin: molecular mechanisms of action associated with chemoresistance. Braz. J. Pharm. Sci. 2014; 50 : 693–701. Publisher Full Text Su SC, Hsieh M, Yang WE, et al. : Cancer metastasis: mechanisms of inhibition by melatonin. J. Pineal Res. 2017; 62 (1) Publisher Full Text Sung H, Ferlay J, Siegel RL, et al. : Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021. May; 71 (3): 209–249. PubMed Abstract | Publisher Full Text Tamura H, Jozaki M, Tanabe M, et al. : Importance of melatonin in assisted reproductive technology and ovarian aging. Int. J. Mol. 2020; 21 . Publisher Full Text Tapia G, Padilla I: Molecular Mechanism of Platinum Resistance in Ovarian Cancer. Ovarian Cancer – A Clinical and Translational Update, Chapter 10. InTech DTP team: Intech; 2013; pp. 205–209. Targhazeh N, Reiter RJ, Rahimi R, et al. : Oncostatic activities of melatonin: Roles in cell cycle, apoptosis, and autophagy. Biochimie. 2022; 200 : 44–59. PubMed Abstract | Publisher Full Text Wang J, Hao H, Yao L, et al. : Melatonin suppresses migration and invasion via inhibition of oxidative stress pathway in glioma cells. J. Pineal Res. 2012; 53 (2): 180–187. Publisher Full Text Woo CJ, Won LJ, Ki KJ, et al. : Splicing variant of AIMP2 as an effective target against chemoresistant in ovarian cancer. J. Mol. Cell Biol. 2012; 4 : 164–173. Publisher Full Text Yeldag G, Rice A, Hernandez AR: Chemoresistance and self-maintaining tumor microenvironment. MDPI. 2018; 10 (12): 471. Publisher Full Text Yi SA, Kim GW, Yoo J, et al. : HP1γ sensitizes cervical cancer cells to cisplatin through the suppression of UBE2L3. Int. J. Mol. Sci. 2020; 21 (17): 5976. PubMed Abstract | Publisher Full Text | Free Full Text Zare H, Shafabakhsh R, Reiter RJ, et al. : Melatonin is a potential inhibitor of ovarian cancer: molecular aspects. J. Ovarian Res. 2019; 12 (1): 26. PubMed Abstract | Publisher Full Text | Free Full Text Zhang X, Hou G, Liu A, et al. : Matrine inhibits the development and progression of ovarian cancer by repressing cancer associated phosphorylation signaling pathways. Cell Death Dis. 2019; 10 : 770. PubMed Abstract | Publisher Full Text | Free Full Text Comments on this article Comments (0) Version 4 VERSION 4 PUBLISHED 21 Mar 2023 ADD YOUR COMMENT Comment Author details Author details 1 Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, Sumatera Utara, 20155, Indonesia 2 Obstetric and Gynecology Department, Fertility Endocrinology Reproduction Division, Medical Faculty, Universitas Sumatera Utara, Medan, Sumatera Utara, 20155, Indonesia 3 Dermatology and Venerology Department, Medical Faculty, Universitas Sumatera Utara, Medan, Sumatera Utara, 20155, Indonesia 4 Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Sumatera Utara, 20155, Indonesia 5 Obstetric and Gynecology Department, Gynecology Oncology Division, Universitas Indonesia, Jakarta, DKI Jakarta, 10430, Indonesia 6 Public Health Faculty, Universitas Indonesia, Jakarta, DKI Jakarta, 10430, Indonesia 7 Obstetric and Gynecology Department, Feto Maternal Division, Medical Faculty, Universitas Sumatera Utara, Medan, Sumatera Utara, 20155, Indonesia 8 Surgery Department, Medical Faculty, Universitas Sumatera Utara, Medan, Sumatera Utara, 20155, Indonesia Cut Adeya Adella Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Resources, Supervision, Writing – Original Draft Preparation M Fidel Ganis Siregar Roles: Formal Analysis, Supervision, Validation, Visualization, Writing – Review & Editing Imam B Putra Roles: Formal Analysis, Project Administration, Supervision, Validation, Writing – Review & Editing Poppy Anjelisa Hasibuan Roles: Formal Analysis, Resources, Supervision, Visualization, Writing – Review & Editing Andrijono Andrijono Roles: Conceptualization, Supervision, Validation, Writing – Review & Editing Adang Bachtiar Roles: Formal Analysis, Supervision, Validation, Writing – Review & Editing Sarma N Lumbanraja Roles: Supervision, Visualization, Writing – Review & Editing Iqbal P Nasution Roles: Supervision, Validation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (4) version 4 Revised Published: 06 Jun 2025, 12:313 https://doi.org/10.12688/f1000research.130172.4 version 3 Revised Published: 02 Sep 2024, 12:313 https://doi.org/10.12688/f1000research.130172.3 version 2 Revised Published: 12 Feb 2024, 12:313 https://doi.org/10.12688/f1000research.130172.2 version 1 Published: 21 Mar 2023, 12:313 https://doi.org/10.12688/f1000research.130172.1 Copyright © 2025 Adeya Adella C et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Adeya Adella C, Siregar MFG, Putra IB et al. Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.12688/f1000research.130172.4 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 4 VERSION 4 PUBLISHED 06 Jun 2025 Revised Views 0 Cite How to cite this report: Artibani M. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r429767 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-429767 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 27 Dec 2025 Mara Artibani , University of Oxford, Oxford, UK Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.183324.r429767 The manuscript examines the effects of melatonin combined with cisplatin in SKOV3 ovarian cancer cells. While the topic is relevant, the study suffers from conceptual, methodological, statistical, and linguistic flaws that prevent any meaningful scientific conclusions. Several issues highlighted by ... Continue reading READ ALL The manuscript examines the effects of melatonin combined with cisplatin in SKOV3 ovarian cancer cells. While the topic is relevant, the study suffers from conceptual, methodological, statistical, and linguistic flaws that prevent any meaningful scientific conclusions. Several issues highlighted by previous reviewers remain unresolved. Major Concerns 1. Inappropriate cell model The authors repeatedly claim to investigate “cisplatin resistance,” yet the only model used is SKOV3 , which is not a cisplatin-resistant ovarian cancer cell line. Resistance is never demonstrated experimentally, nor are resistant vs sensitive models compared. 2. Experimental design cannot test resistance Melatonin and cisplatin were added simultaneously for 48 hours. This measures acute cytotoxicity only. It does not model: acquired resistance intrinsic resistance reversal or inhibition of resistance 3. Misuse and misunderstanding of IC50 Terms such as “1× IC50,” “¾× IC50,” etc. are used as if IC50 were a standardized dose unit, rather than a calculated concentration. This is conceptually incorrect. The combination dosing strategy is unjustified and difficult to interpret. 4. Lack of mechanistic evidence Although the Discussion lists numerous pathways (AKT, JNK, MMP-9, NF-κB, BAX/BCL-2, etc.), none are evaluated experimentally. The only measurements made are: CTR1, Pgp, GSH, ERCC1, E-cadherin, Annexin V. All via single-parameter flow cytometry, without orthogonal validation (e.g., Western blots). This is insufficient to support mechanistic claims. 6. Statistical and interpretive errors In key comparisons (e.g., Pgp, GSH), the combination (C1) is not significantly different from melatonin alone. Yet the manuscript claims the combination “reduces efflux” or “reduces drug inactivation.” This is incorrect: in several cases, melatonin alone accounts for the effect. Additionally, many effect sizes are small and likely not biologically meaningful. 7. Methodological problems No explanation of flow cytometry gating, live/dead exclusion, or compensation. No validation of antibody specificity. Critical details omitted; trivial procedural steps over-described. Disturbing methodological phrasing (e.g., implying 70% ethanol was present in culture flasks) suggests poor proofreading or conceptual errors. 8. Writing quality and use of scientific language The manuscript exhibits extensive issues: Frequent grammatical errors (e.g., “it’s” vs “its”). Non-standard terminology (“variables” for treatments, “laboratory experiment”). Inconsistent units (mM vs μM). Unclear or awkward phrasing. Overly long explanations of irrelevant details and insufficient explanation of essential methods. 9. Overstated conclusions The manuscript concludes that melatonin “reduces chemoresistance” and modulates multiple resistance pathways. Given the inappropriate model, flawed design, and weak data, these statements are unsupported and should not be made. Minor Concerns Figures lack two-parameter cytometry plots. The Limitations section remains incomplete despite revisions. The Discussion is overly long and contains speculative content not grounded in the study's findings. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? No Competing Interests: No competing interests were disclosed. Reviewer Expertise: Ovarian cancer I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Artibani M. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r429767 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-429767 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Umran TUNC C. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r427782 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-427782 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 11 Dec 2025 Cansu Umran TUNC , The University of Utah, Salt Lake City, Utah, USA Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.183324.r427782 The paper discusses the potential effect of the combination of melatonin and cisplatin treatment on cisplatin resistance in ovarian cancer. The study presents data on viability and potential drug resistance pathways. It gives some insights into the combination therapy. However, ... Continue reading READ ALL The paper discusses the potential effect of the combination of melatonin and cisplatin treatment on cisplatin resistance in ovarian cancer. The study presents data on viability and potential drug resistance pathways. It gives some insights into the combination therapy. However, the paper is poorly written. The introduction is insufficient to explain the hypothesis, aims, and outcomes of the study. The results were not discussed at all. The experimental design should include a drug-resistant cell line to draw a conclusion. The protein analysis did not reveal any significant differences between the combination groups and single treatment groups. The authors should calculate the combination index using an appropriate method to understand whether the effect is additive, combinatorial, or antagonistic. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Drug delivery, gene therapy, combination drug therapy, and molecular biology I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Umran TUNC C. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r427782 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-427782 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Brancewicz J. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r429776 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-429776 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 08 Dec 2025 Jan Brancewicz , Cellis R&D, Cellis, Warsaw, Poland Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.183324.r429776 Dear Authors, Thank you for your submission. While your topic is of potential interest, the manuscript requires substantial revision in study design, methodological accuracy, data presentation, figure quality, and English usage. Please find my detailed comments below, ... Continue reading READ ALL Dear Authors, Thank you for your submission. While your topic is of potential interest, the manuscript requires substantial revision in study design, methodological accuracy, data presentation, figure quality, and English usage. Please find my detailed comments below, organized according to the structure of your manuscript. General Evaluation The overall presentation of this work remains scientifically immature. Data visualization is the main weakness: results are presented in raw tables that are difficult to interpret, with statistical outcomes detached from figures and not shown graphically. The study relies on a single cell line (SKOV-3), which makes the conclusions unreliable and not generalizable to ovarian cancer biology. Methodological details are incomplete, and flow cytometry protocols deviate from accepted standards, affecting reproducibility. Furthermore, the discussion is mostly a literature summary and fails to contextualize or critically interpret the presented data. Finally, the English language requires extensive professional revision to correct grammar, syntax, and terminology, avoiding both colloquial expressions (“each cell was exposed to each material”) and inconsistent scientific notation (“ethanol 70%,” “5% CO2,” “tripsin,” etc.). Section-by-Section Comments Introduction (Page 3) – Grammar: “modulates” instead of “modulate.” – “Melatonin has a good effect on clinical outcomes…” - this statement requires a supporting reference. – The text contains redundant and stylistically awkward phrasing; revise for clarity and conciseness. – The introduction should better define the rationale of using melatonin with cisplatin in cisplatin-resistant ovarian cancer and explicitly describe the hypothesis tested. Materials and Methods (Pages 4–6) General remarks – The description of the experimental workflow is confusing and sometimes inaccurate. Please clearly separate (i) cell culture maintenance, (ii) treatment scheme, (iii) IC50 determination, and (iv) flow cytometry analyses. – Provide complete details to ensure reproducibility: antibody clones, fluorophores, concentrations/dilutions, solvents, manufacturers, and whether compensation was applied. – Replace rpm values with relative centrifugal force (× g) or provide rotor radius. – Use correct scientific notation and proper typographical style (e.g., 70% ethanol, 5% CO₂, 37 °C). – Institutions where experiments were performed should be mentioned in Acknowledgements, not in Methods. Delete time information as well. Specific remarks – Page 4, paragraph 1: Correct “tripsin” to “trypsin.” – Page 4, line 5: Remove redundant mention of experiment dates and locations; cite only ethical approval code. – Page 4, “IC50 determination”: “Solutions” of what? Please specify whether these refer to drug dilutions or stock solutions. – Indicate the number of biological replicates (n) per group and the number of technical replicates per assay. – “GraphPad software was used to analyze the IC50 values.” - Specify which version, which regression model, and statistical parameters (e.g., non-linear fit, R²). – Describe the criteria for IC50 derivation (interpolation, nonlinear regression, etc.). – Provide justification for the concentration ranges used. – Page 5, “Cytotoxic activity”: a) Replace colloquial “each cell was exposed to each material” with “each cell line was treated with reagents as described in Table 1.” b) Use “Gibco” instead of “Gibsco.” c) Replace “ethanol 70%” with “70% ethanol.” d) Replace “the solution was read” with “absorbance was measured.” e) The explanation of MTS assay principle is unnecessary and may be removed. – Page 5, “Preparation of cell for flow cytometry”: rename to “Preparation of samples for flow cytometry.” – Clarify the exact buffer composition and manufacturer (e.g., “stain buffer (BD Biosciences, Cat. no. 554656)”). – Page 5–6, “Flow cytometry of CTR-1 and P-gp / GSH / ERCC1 / E-cadherin / Annexin V”: a) The use of room-temperature or 37 °C antibody incubation is non-canonical and introduces non-specific binding. These steps must be performed on ice (4 °C). b) State explicitly whether cells were live-stained or fixed/permeabilized; name the fixation buffer (e.g., “Cytofix/Cytoperm, BD Biosciences”) and manufacturer. c) Define whether values represent percentages of marker-positive live cells or total events. d) Indicate gating strategy, compensation controls, and whether isotype controls were used. e) Clarify the meaning of “permwash buffer”; give manufacturer and catalog number. f) Provide antibody clones, conjugates, and catalog numbers for all targets (CTR-1, P-gp, GSH, ERCC-1, E-cadherin, Annexin V). – Page 6, “Statistical analysis”: a) Describe tests for normality and variance (e.g., Shapiro-Wilk, Levene’s). b) State whether p-values were two-tailed and corrected for multiple comparisons. c) Define how data are expressed (mean ± SD or SEM). d) Specify software precisely: “SPSS v21.0 (IBM, Armonk, NY, USA).” e) Add sample sizes (n) for each group. Results (Pages 6–11) – The section begins redundantly (“In this study, SKOV3 cells were used.”); delete this sentence. – Authors used only one cell line (SKOV-3) whereas they should consider using the panel of 4-5 of them (e.g. ATCC TCP-1021 and OVCAR-4), some of which are cisplatin resistant, and some which are cisplatin sensitive. – Photographs in Figures 1–2 are of poor quality and must be replaced with high-resolution micrographs. – Merge Figures 1 and 2, as they both present microscopy. – Table 1 lacks consistency with text (C1–C4 naming); unify across manuscript. – Change “Cell culture was observed” to “Cells were photographed.” – Tables 2–8 should be replaced with graphs showing mean ± SD, n, and statistical annotations (stars or symbols). – Clarify whether data represent percentages of marker-positive cells or mean fluorescence intensities (MFI). – Always specify: (i) test used, (ii) n biological replicates, (iii) n technical replicates, (iv) type of error bars, (v) reference group for significance. – Table 2 – Add SD/SE; explain “Medium control 0%” and number of replicates. – Tables 3–8 – Provide SD/SE values and make sure all statistical comparisons correspond to figure symbols. – CTR1 section: Authors should also compare C1 vs C4 groups; currently only comparisons vs single agents are shown. – P-gp section: The “IC Doxorubicin” group cannot realistically have 0.0 % P-gp expression if viability > 0; add FMO control and address this inconsistency. – Throughout Results, avoid imprecise language such as “chemotherapy influx” - refer to specific drug (cisplatin or doxorubicin). – Replace “dry” tables with summarized figures and combine all data (Tables 2–8) into a single multi-panel figure for clarity. Discussion (Pages 12–14) – The first paragraph repeats sentences verbatim: “Melatonin exhibits anti-inflammatory, anti-tumor, and anti-proliferative activities…” - delete duplication. – Add reference supporting the claim that melatonin has “minimal side effects.” – The term “single-use therapy” is non-scientific and should be replaced with “monotherapy.” – The Discussion merely lists literature facts about CTR1, P-gp, GSH, etc., but does not confront them with your own results. Revise to discuss how your findings agree or conflict with prior studies. – Clarify what is novel in your dataset relative to the cited works. – Avoid repeating descriptions of published mechanisms without connecting them to your data. – Extend the section summarizing limitations (cell-line restriction, lack of validation, non-orthogonal confirmation of flow cytometry by Western blot, etc.) - this is essential for transparency and scientific maturity. Conclusion (Page 14) – The conclusions are generally aligned with the data shown but overstate the certainty of findings. – Emphasize that results are preliminary and limited to one cell line; avoid causal language (“may reduce chemoresistance” instead of “reduce”). – Indicate that further validation using additional cell lines and in vivo studies is required. Data Availability and References – Ensure all Mendeley, protocols.io and DOI links are functional. – Clearly describe the content of each dataset (raw .csv files, flow cytometry .fcs files, microscopy .tif images). – Unify reference style (PubMed/DOI consistency). – Verify that all statements in the text are properly referenced. Language and Formatting Issues The manuscript contains numerous grammatical and stylistic errors, including: – “cell was centrifuged” → “cells were centrifuged” (repeated error throughout) – “in each cell” → “in each cell line” – “cell solution” instead of “cell suspension” – Replace “flowcytometry” with “flow cytometry” everywhere. – Maintain consistent tense (past for Methods, present for Results/Discussion). A thorough language edit by a native or professional scientific editor is mandatory before resubmission. Overall Assessment The study’s premise is potentially interesting, but methodological rigor, data visualization, and clarity fall short of scientific standards. The use of only one cell line, incomplete methodological information, non-standard flow cytometry protocols, and poor figure quality severely limit reproducibility and interpretation. The Discussion must be rewritten to critically evaluate the results against existing literature. Until these issues are comprehensively addressed, the manuscript cannot be recommended for indexing. Best regards, Jan Brancewicz Is the work clearly and accurately presented and does it cite the current literature? No Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? No If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? No Competing Interests: No competing interests were disclosed. Reviewer Expertise: My research focuses on cell biology and translational medicine, combining wet-lab experimental work with quantitative data analysis. I study the interactions between immune cells and cancer, particularly macrophage-based therapies for solid tumors, integrating molecular and cellular assays, microscopy, and statistical evaluation of preclinical data to support the development of innovative therapeutic approaches. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Brancewicz J. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r429776 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-429776 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Rodland K. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r396249 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-396249 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 09 Aug 2025 Karin Rodland , Oregon Health & Science University, Portland, Oregon, USA Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.183324.r396249 The manuscript ‘Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer’, has made the interesting observation that treating SKOV3 cells with combinations of millimolar melatonin and micromolar cisplatin resulted in decreased cell viability ... Continue reading READ ALL The manuscript ‘Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer’, has made the interesting observation that treating SKOV3 cells with combinations of millimolar melatonin and micromolar cisplatin resulted in decreased cell viability and increased apoptosis compared to either agent alone. However, despite several rounds of revision, the manuscript is still significantly flawed and has failed to address the most serious concerns expressed in prior reviews. First, the use of a single cell line, SKOV3, is essentially a fatal flaw which cannot be adequately dealt with simply by acknowledging that it would be better to use more cell lines. One simply cannot say anything about the effects of melatonin on cisplatin resistance without comparing sensitive and resistance cell populations. As the researchers had the resources to do multiple replicates of the experiment, per the text, and include partial combinations of cisplatin and melatonin that are difficult to defend logically, it should have been possible to perform the key experiments on at least a second cell line. The fundamental design of the experiments also brings up another problem. By adding melatonin and cisplatin concurrently, and harvesting the cells 48 hours later, it is unclear whether the authors are proposing that melatonin will delay the development of platinum resistance or provide an alternative mechanism for cell death in cells that are already cisplatin resistant. This is a crucial question in the context of potential clinical relevance, which appears to be the justification for these experiments based on the abstract and introduction. If the concept is to treat ovarian cancers that are known to be platinum resistant or refractory, then the data presented clearly show that melatonin, alone or in conjunction with cisplatin, is substantially inferior to doxorubicin alone, a clinically tested and approved second line therapy for platinum resistant ovarian cancer. The third problem is that we learn nothing about the mechanisms of action of melatonin, alone or in conjunction with cisplatin, from these experiments. The decision to measure CTR1, Pgp, and GSH implies the hypothesis that melatonin has the potential to act via traditional mechanisms of drug influx, efflux, and/or inactivation, but in all these experiments there is no statistically significant difference between melatonin alone and melatonin + cisplatin; therefore, hypotheses related to drug metabolism are disproven, but that is never discussed. In response to prior reviews, the authors have increased their citations relating to actions of melatonin in other systems, including the naming of cellular pathways shown to be modulated in other publications, but there is no attempt to measure any of these endpoints in their experimental system. This is a major limitation of the choice of flow cytometry as the primary measurement platform. Had the authors chosen to prepare Western blots, the same membrane could have been probed with a large number of antibodies to establish possible changes in MMP-9, AKT, JNK1/2, ERK1/2, and other potential pathways. Annexin-V and E-cadherin could have been easily measured in Western blots, providing orthogonal validation of the flow cytometry results. Minor errors in the manuscript include: Identification of SKOV3 as a clear cell ovarian cancer when it is a serious adenocarcinoma The abstract uses mM to define the IC50 for melatonin, cisplatin, and doxorubicin, whereas the text gives the IC50 for cisplatin and doxorubicin in uM. If the IC50s are truly in mM, then the use of 4 significant figures for melatonin is inappropriate. Most analytical chemists would like to see justification for 4 significant figures, given that the doses administered were only accurate to 2 significant figures. Since all of the quantification was given as ‘per cent labeled cells’ by flow cytometry, the Methods section needs to be absolutely clear that this is ‘per centage of live cells’, as including dead cells in the analysis could have biased the results, given the differences in cell viability Again, given that all protein measurements were made by flow cytometry, it would have been nice to see two-axis flow diagrams, at the very least for ERCC1 and E-cadherin, which were apparently measured simultaneously. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: cancer cell biology, specifically ovarian and breast cancers; cancer proteogenomics; cancer biomarkers I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Rodland K. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r396249 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-396249 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Tortelli TC. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r390100 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-390100 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 25 Jun 2025 Tharcisio C. Tortelli , Universidade de Sao Paulo, Sao Paulo, Brazil Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.183324.r390100 Thank you for the answers but some of the problems remains. Some of the conclusions like P-glycoprotein expression and GSH level have no correspond in the results because the melatonin IC50 is equal to the combination of CIS + melatonin. ... Continue reading READ ALL Thank you for the answers but some of the problems remains. Some of the conclusions like P-glycoprotein expression and GSH level have no correspond in the results because the melatonin IC50 is equal to the combination of CIS + melatonin. The result show that is pointless to add cisplatin in these cases. Also, by using one cell line, being cisplatin-resistant or not, the author cannot generalize the results to ovarian cancer. This is a huge step. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Cell biology and develpment of new treatments for cancer therapy. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Tortelli TC. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r390100 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-390100 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 3 VERSION 3 PUBLISHED 02 Sep 2024 Revised Views 0 Cite How to cite this report: Souček P. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.171173.r319904 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v3#referee-response-319904 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 11 Sep 2024 Pavel Souček , Charles University, Pilsen, Czech Republic Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.171173.r319904 The authors reflected some of my criticisms. On the other hand, the most serious concerns remain unresolved. I understand that adding another cell line would substantially shift the paper indexing period. However, at least a statement that the results ... Continue reading READ ALL The authors reflected some of my criticisms. On the other hand, the most serious concerns remain unresolved. I understand that adding another cell line would substantially shift the paper indexing period. However, at least a statement that the results need verification using other cell lines should be placed in the Discussion under the study limitations section. This section is actually missing and should be included. Additionally, the fact that I have pointed out, i.e. that the observed changes between treatments are too small to be biologically relevant was left unattended. Again, to make this report more plausible, the statement that observations are just indicative or hypothesis-generating and have to be confirmed by many additional studies has to be added to the above-mentioned study limitations. The authors should frankly list such studies, i.e. search for conditions giving more robust differences, defining the relevant mechanism behind them (because the list of all pathways in the Conclusion is hardly acceptable - some can be drivers and other just consequences), and finally confirmation by in vivo experiment where the bioavailability of dosing should also be tested. The Discussion section should be reconstructed accordingly. Competing Interests: No competing interests were disclosed. Reviewer Expertise: cancer biology I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Souček P. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.171173.r319904 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v3#referee-response-319904 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 17 Sep 2024 Cut Adeya Adella , Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia 17 Sep 2024 Author Response Thank you for the suggestion, may i ask - should i also add the bioavailability of dosing that should also be tested by in vivo and confirm it in the ... Continue reading Thank you for the suggestion, may i ask - should i also add the bioavailability of dosing that should also be tested by in vivo and confirm it in the limitations ? - what else in the discussion site that should be reconstructed so i can make all of the suggestions included in the revision ? Thank you Thank you for the suggestion, may i ask - should i also add the bioavailability of dosing that should also be tested by in vivo and confirm it in the limitations ? - what else in the discussion site that should be reconstructed so i can make all of the suggestions included in the revision ? Thank you Competing Interests: No competing interests were disclosed. Close Report a concern Author Response 11 Aug 2025 Cut Adeya Adella , Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia 11 Aug 2025 Author Response Thank you for the comment and correction, i also apologize for the late respond of your revision. I have added the limitation section in the new correction. It is ... Continue reading Thank you for the comment and correction, i also apologize for the late respond of your revision. I have added the limitation section in the new correction. It is important to show that this study need to be expanded and developed so it can show the melatonin effect on other cell line. I have added the statement this result may need to other study to confirm and verificate the effect of melatonin on other cell line. I have also added the statement that the statement that observations are just indicative or hypothesis-generating and have to be confirmed by many additional studies and statement that it must be performed in vivo to see the bioavailability of dosing in limitation section. The conclusion section have been corrected. I have added several studies that explain melatonin mechanism in chemoresistance in the discussion section and corrected the conclusion section. Once again, i greatly appreciate the suggestion and look forward for your comment Thank you for the comment and correction, i also apologize for the late respond of your revision. I have added the limitation section in the new correction. It is important to show that this study need to be expanded and developed so it can show the melatonin effect on other cell line. I have added the statement this result may need to other study to confirm and verificate the effect of melatonin on other cell line. I have also added the statement that the statement that observations are just indicative or hypothesis-generating and have to be confirmed by many additional studies and statement that it must be performed in vivo to see the bioavailability of dosing in limitation section. The conclusion section have been corrected. I have added several studies that explain melatonin mechanism in chemoresistance in the discussion section and corrected the conclusion section. Once again, i greatly appreciate the suggestion and look forward for your comment Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 17 Sep 2024 Cut Adeya Adella , Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia 17 Sep 2024 Author Response Thank you for the suggestion, may i ask - should i also add the bioavailability of dosing that should also be tested by in vivo and confirm it in the ... Continue reading Thank you for the suggestion, may i ask - should i also add the bioavailability of dosing that should also be tested by in vivo and confirm it in the limitations ? - what else in the discussion site that should be reconstructed so i can make all of the suggestions included in the revision ? Thank you Thank you for the suggestion, may i ask - should i also add the bioavailability of dosing that should also be tested by in vivo and confirm it in the limitations ? - what else in the discussion site that should be reconstructed so i can make all of the suggestions included in the revision ? Thank you Competing Interests: No competing interests were disclosed. Close Report a concern Author Response 11 Aug 2025 Cut Adeya Adella , Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia 11 Aug 2025 Author Response Thank you for the comment and correction, i also apologize for the late respond of your revision. I have added the limitation section in the new correction. It is ... Continue reading Thank you for the comment and correction, i also apologize for the late respond of your revision. I have added the limitation section in the new correction. It is important to show that this study need to be expanded and developed so it can show the melatonin effect on other cell line. I have added the statement this result may need to other study to confirm and verificate the effect of melatonin on other cell line. I have also added the statement that the statement that observations are just indicative or hypothesis-generating and have to be confirmed by many additional studies and statement that it must be performed in vivo to see the bioavailability of dosing in limitation section. The conclusion section have been corrected. I have added several studies that explain melatonin mechanism in chemoresistance in the discussion section and corrected the conclusion section. Once again, i greatly appreciate the suggestion and look forward for your comment Thank you for the comment and correction, i also apologize for the late respond of your revision. I have added the limitation section in the new correction. It is important to show that this study need to be expanded and developed so it can show the melatonin effect on other cell line. I have added the statement this result may need to other study to confirm and verificate the effect of melatonin on other cell line. I have also added the statement that the statement that observations are just indicative or hypothesis-generating and have to be confirmed by many additional studies and statement that it must be performed in vivo to see the bioavailability of dosing in limitation section. The conclusion section have been corrected. I have added several studies that explain melatonin mechanism in chemoresistance in the discussion section and corrected the conclusion section. Once again, i greatly appreciate the suggestion and look forward for your comment Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Tortelli TC. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.171173.r319902 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v3#referee-response-319902 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 04 Sep 2024 Tharcisio C. Tortelli , Universidade de Sao Paulo, Sao Paulo, Brazil Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.171173.r319902 Thank you for the answers. The conclusion is wrong for some of the results. For PGP expression, the authors cannot say that the combination works because there is no statistical difference between C1 group and IC50mel. This ... Continue reading READ ALL Thank you for the answers. The conclusion is wrong for some of the results. For PGP expression, the authors cannot say that the combination works because there is no statistical difference between C1 group and IC50mel. This way, why adding cisplatin? The effect observed is due to melatonin only. The same conclusion works for GSH where again, there is no statistical difference between C1 group and IC50mel. The point of my first review is that the combination must be better than cisplatin and melatonin treatment alone. Any other situation shows that the combination is not necessary because there was no improvement when adding the other drug. The conclusion is too strong for the results. Despite the use of the term “may”, it is too early to assume anything because there is no functional assay. Also, the conclusion is too generic as the experiments were done in just one cell line. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Cell biology and develpment of new treatments for cancer therapy. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Tortelli TC. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.171173.r319902 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v3#referee-response-319902 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 10 Sep 2025 Cut Adeya Adella , Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia 10 Sep 2025 Author Response First of all, i apologize for the late respond of your comment. I appreciate your correction. P glycoprotein is a transmembrane glycoprotein as an efflux transporter specifically for chemotherapy. Higher ... Continue reading First of all, i apologize for the late respond of your comment. I appreciate your correction. P glycoprotein is a transmembrane glycoprotein as an efflux transporter specifically for chemotherapy. Higher PgP percentage indicates that cytotoxic agent is inhibited to entry into the cell and may reduce the effect of chemotherapy in cancer cell, so the resistance is high. In this result, it was shown from the Bonferroni test, between IC50 melatonin and Pgp also IC50 melatonin and GSH, there were statistically no difference. We performed the Bonferroni to show which pair variables have significantly different. The main purpose of this research was to shown that C1 group (combination of 1x IC50 melatonin and 1x IC50 cisplatin) was better than IC50 cisplatin alone, and from the result there was significant different in each markers of ovarian resistance. I have included the explanation about those that were no difference in the result part. Because we performed it in SKOV 3 in this first experiment in cisplatin resistance ovarian cancer, in the next research it would be better to use this combination in other ovarian cancer cell line that resistant to cisplatin. I have added the suggestion in the conclusion part. Thank you for the suggestion and correction. I look forward for your comment. First of all, i apologize for the late respond of your comment. I appreciate your correction. P glycoprotein is a transmembrane glycoprotein as an efflux transporter specifically for chemotherapy. Higher PgP percentage indicates that cytotoxic agent is inhibited to entry into the cell and may reduce the effect of chemotherapy in cancer cell, so the resistance is high. In this result, it was shown from the Bonferroni test, between IC50 melatonin and Pgp also IC50 melatonin and GSH, there were statistically no difference. We performed the Bonferroni to show which pair variables have significantly different. The main purpose of this research was to shown that C1 group (combination of 1x IC50 melatonin and 1x IC50 cisplatin) was better than IC50 cisplatin alone, and from the result there was significant different in each markers of ovarian resistance. I have included the explanation about those that were no difference in the result part. Because we performed it in SKOV 3 in this first experiment in cisplatin resistance ovarian cancer, in the next research it would be better to use this combination in other ovarian cancer cell line that resistant to cisplatin. I have added the suggestion in the conclusion part. Thank you for the suggestion and correction. I look forward for your comment. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 10 Sep 2025 Cut Adeya Adella , Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia 10 Sep 2025 Author Response First of all, i apologize for the late respond of your comment. I appreciate your correction. P glycoprotein is a transmembrane glycoprotein as an efflux transporter specifically for chemotherapy. Higher ... Continue reading First of all, i apologize for the late respond of your comment. I appreciate your correction. P glycoprotein is a transmembrane glycoprotein as an efflux transporter specifically for chemotherapy. Higher PgP percentage indicates that cytotoxic agent is inhibited to entry into the cell and may reduce the effect of chemotherapy in cancer cell, so the resistance is high. In this result, it was shown from the Bonferroni test, between IC50 melatonin and Pgp also IC50 melatonin and GSH, there were statistically no difference. We performed the Bonferroni to show which pair variables have significantly different. The main purpose of this research was to shown that C1 group (combination of 1x IC50 melatonin and 1x IC50 cisplatin) was better than IC50 cisplatin alone, and from the result there was significant different in each markers of ovarian resistance. I have included the explanation about those that were no difference in the result part. Because we performed it in SKOV 3 in this first experiment in cisplatin resistance ovarian cancer, in the next research it would be better to use this combination in other ovarian cancer cell line that resistant to cisplatin. I have added the suggestion in the conclusion part. Thank you for the suggestion and correction. I look forward for your comment. First of all, i apologize for the late respond of your comment. I appreciate your correction. P glycoprotein is a transmembrane glycoprotein as an efflux transporter specifically for chemotherapy. Higher PgP percentage indicates that cytotoxic agent is inhibited to entry into the cell and may reduce the effect of chemotherapy in cancer cell, so the resistance is high. In this result, it was shown from the Bonferroni test, between IC50 melatonin and Pgp also IC50 melatonin and GSH, there were statistically no difference. We performed the Bonferroni to show which pair variables have significantly different. The main purpose of this research was to shown that C1 group (combination of 1x IC50 melatonin and 1x IC50 cisplatin) was better than IC50 cisplatin alone, and from the result there was significant different in each markers of ovarian resistance. I have included the explanation about those that were no difference in the result part. Because we performed it in SKOV 3 in this first experiment in cisplatin resistance ovarian cancer, in the next research it would be better to use this combination in other ovarian cancer cell line that resistant to cisplatin. I have added the suggestion in the conclusion part. Thank you for the suggestion and correction. I look forward for your comment. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Version 2 VERSION 2 PUBLISHED 12 Feb 2024 Revised Views 0 Cite How to cite this report: Souček P. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.160652.r291392 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v2#referee-response-291392 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 27 Jun 2024 Pavel Souček , Charles University, Pilsen, Czech Republic Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.160652.r291392 The authors of the paper Cut Adeya Adella et al. report the results of an in vitro study of a combination regimen composed of cisplatin and melatonin in an ovarian cancer SKOV3 cell line model. They conclude that the combination ... Continue reading READ ALL The authors of the paper Cut Adeya Adella et al. report the results of an in vitro study of a combination regimen composed of cisplatin and melatonin in an ovarian cancer SKOV3 cell line model. They conclude that the combination of melatonin with cisplatin at a dose close to IC 50 decreases cell viability, increases protein expression of influx transporter CTR1, and reduces that of efflux p-glycoprotein. Other markers changed by this combination include a reduced GSH level and ERCC1 protein expression. The observed increase of E-cadherin expression suggested a potential slowdown of epithelial-mesenchymal transition, and annexin V staining points to stimulation of apoptosis. The findings, if confirmed by independent studies and different approaches, can be interesting for the next phase of preclinical research in this area. The content of the paper suits well to the scope of the F1000 journal. Major criticisms 1/ Although potentially interesting and important, the results rely on findings made only using one cell line, which does not robustly represent ovarian cancer. Experiments on two or three cell lines are recommended for in vitro studies. Also, the claim that SKOV3 represents resistant ovarian cancer is not enough. Optimally, experiments on sensitive and resistant subclones of the same cell line would be needed to show some differences and specificity of observed effects for resistant models. 2/ The data in Table 2 show that the effect of combinations on cell viability is very mild – between 37.6 and 48.4% compared to 47.7% for melatonin and 55.2% for cisplatin alone. How biologically relevant is such synergy? The same applies to the C1 combination regarding PgP expression (Table 4) and GSH level (Table 5), which are not much different from melatonin alone. 3/ Why doxorubicin was used as “positive control”? This drug is not used in ovarian cancer treatment at all. Mechanisms of action are completely different from platinum derivatives. 4/ Why cell cycle was not followed? The rest of the experiments were done by flow cytometry anyway, and melatonin or cisplatin did not cause much apoptosis. 5/ The Discussion section contains several controversial statements, e.g., “High e-cadherin was associated with high activities of invasive cancer and metastasis (Loh et al., 2019).“ Further: “Melatonin administration increased e-cadherin expression... Melatonin may decrease the migration and invasion activities of cancer cells (Goncalves et al., 2016).“ Moreover, in the present study, C1 increased E-cadherin over cisplatin or melatonin alone (Fig. 7). So, is high E-cadherin good or bad for eventual patients? Overall, the discussion would profit from the scheme of the main effect or mechanism behind the C1 combination. Minor comments 6/ Statistical tests should be described in Methods. 7/ GSH should be referred to as peptide, and terms level or concentration better reflect its amount than “expression”. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: cancer biology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Souček P. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.160652.r291392 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v2#referee-response-291392 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 29 Aug 2024 Cut Adeya Adella , Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia 29 Aug 2024 Author Response First of all, I am really grateful for the correction in this review, and also I would like to apologize for the late response This study was performed ... Continue reading First of all, I am really grateful for the correction in this review, and also I would like to apologize for the late response This study was performed to prove that combination of melatonin and cisplatin in ovarian cancer had significant result in resistant ovarian cancer. We used SKOV 3 cell line which was ovarian cancer cell line that resemble with clear cell adenocarcinoma of ovary, this cell line was resistant to platinum chemotherapy such as cisplatin ; as we know that platinum group of chemotherapy is the first line in ovarian cancer treatment. Because of this, we only used SKOV 3 cell line (ATCC HTB-77) (cell that resistant to cisplatin treatment) and combination of melatonin and cisplatin to potentiate the effect in inhibition of the resistance. This might be good opportunity for other researcher to investigate and explore this research while using cell line that sensitive and resistant cell type, to improve the result. In this study, we compared the cisplatin, melatonin, and several combination of cisplatin and melatonin in various concentration, all of the result in this study shown that combination of cisplatin and melatonin in C1 group was superior than other combination groups; also with cisplatin and melatonin groups alone. In cell viability result, we would like to show that C1 group (37.57%) could reduce SKOV 3 cell viability which is why it was a good sign that combination of melatonin and cisplatin may inhibit the resistant ovarian cancer cell better than melatonin alone. The same result was also applied in C1 group of Pgp expression and GSH level compared to melatonin alone. The result was to show that combination of melatonin and cisplatin was better than melatonin, cisplatin, and doxorubicin alone. We used doxorubicin as the positive control, because doxorubicin act as second line drug of choice in platinum resistant ovarian cancer. We did not check the cell cycle activity because the aim of this study was to measure inhibition of resistant ovarian cancer cell using several parameters such as cell viability, CTR1, Pgp, GSH, ERCC1, e-cadherin, and Annexin V, because there was also limitation in funding. Further, for other researcher that interest with this study, may add the cell cycle and performed better examination for the improvement and better result. For apoptosis activity, we used annexin V parameter ; which is high level of annexin V indicates high apoptosis activity. In the result, it was shown that combination of melatonin and cisplatin groups in various concentration were better than cisplatin and melatonin alone ; (Annexin V level in C1 = 53.57 ; IC50 melatonin = 15.77 ; and cisplatin = 10.87). Thank you for the correction, it should be high e-cadherin level was associated with lower cell invasion and metastasis. I will correct it in the manuscript. For the 6 and 7 questions, I will gladly correct and add your revision in the manuscript. Thank you First of all, I am really grateful for the correction in this review, and also I would like to apologize for the late response This study was performed to prove that combination of melatonin and cisplatin in ovarian cancer had significant result in resistant ovarian cancer. We used SKOV 3 cell line which was ovarian cancer cell line that resemble with clear cell adenocarcinoma of ovary, this cell line was resistant to platinum chemotherapy such as cisplatin ; as we know that platinum group of chemotherapy is the first line in ovarian cancer treatment. Because of this, we only used SKOV 3 cell line (ATCC HTB-77) (cell that resistant to cisplatin treatment) and combination of melatonin and cisplatin to potentiate the effect in inhibition of the resistance. This might be good opportunity for other researcher to investigate and explore this research while using cell line that sensitive and resistant cell type, to improve the result. In this study, we compared the cisplatin, melatonin, and several combination of cisplatin and melatonin in various concentration, all of the result in this study shown that combination of cisplatin and melatonin in C1 group was superior than other combination groups; also with cisplatin and melatonin groups alone. In cell viability result, we would like to show that C1 group (37.57%) could reduce SKOV 3 cell viability which is why it was a good sign that combination of melatonin and cisplatin may inhibit the resistant ovarian cancer cell better than melatonin alone. The same result was also applied in C1 group of Pgp expression and GSH level compared to melatonin alone. The result was to show that combination of melatonin and cisplatin was better than melatonin, cisplatin, and doxorubicin alone. We used doxorubicin as the positive control, because doxorubicin act as second line drug of choice in platinum resistant ovarian cancer. We did not check the cell cycle activity because the aim of this study was to measure inhibition of resistant ovarian cancer cell using several parameters such as cell viability, CTR1, Pgp, GSH, ERCC1, e-cadherin, and Annexin V, because there was also limitation in funding. Further, for other researcher that interest with this study, may add the cell cycle and performed better examination for the improvement and better result. For apoptosis activity, we used annexin V parameter ; which is high level of annexin V indicates high apoptosis activity. In the result, it was shown that combination of melatonin and cisplatin groups in various concentration were better than cisplatin and melatonin alone ; (Annexin V level in C1 = 53.57 ; IC50 melatonin = 15.77 ; and cisplatin = 10.87). Thank you for the correction, it should be high e-cadherin level was associated with lower cell invasion and metastasis. I will correct it in the manuscript. For the 6 and 7 questions, I will gladly correct and add your revision in the manuscript. Thank you Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 29 Aug 2024 Cut Adeya Adella , Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia 29 Aug 2024 Author Response First of all, I am really grateful for the correction in this review, and also I would like to apologize for the late response This study was performed ... Continue reading First of all, I am really grateful for the correction in this review, and also I would like to apologize for the late response This study was performed to prove that combination of melatonin and cisplatin in ovarian cancer had significant result in resistant ovarian cancer. We used SKOV 3 cell line which was ovarian cancer cell line that resemble with clear cell adenocarcinoma of ovary, this cell line was resistant to platinum chemotherapy such as cisplatin ; as we know that platinum group of chemotherapy is the first line in ovarian cancer treatment. Because of this, we only used SKOV 3 cell line (ATCC HTB-77) (cell that resistant to cisplatin treatment) and combination of melatonin and cisplatin to potentiate the effect in inhibition of the resistance. This might be good opportunity for other researcher to investigate and explore this research while using cell line that sensitive and resistant cell type, to improve the result. In this study, we compared the cisplatin, melatonin, and several combination of cisplatin and melatonin in various concentration, all of the result in this study shown that combination of cisplatin and melatonin in C1 group was superior than other combination groups; also with cisplatin and melatonin groups alone. In cell viability result, we would like to show that C1 group (37.57%) could reduce SKOV 3 cell viability which is why it was a good sign that combination of melatonin and cisplatin may inhibit the resistant ovarian cancer cell better than melatonin alone. The same result was also applied in C1 group of Pgp expression and GSH level compared to melatonin alone. The result was to show that combination of melatonin and cisplatin was better than melatonin, cisplatin, and doxorubicin alone. We used doxorubicin as the positive control, because doxorubicin act as second line drug of choice in platinum resistant ovarian cancer. We did not check the cell cycle activity because the aim of this study was to measure inhibition of resistant ovarian cancer cell using several parameters such as cell viability, CTR1, Pgp, GSH, ERCC1, e-cadherin, and Annexin V, because there was also limitation in funding. Further, for other researcher that interest with this study, may add the cell cycle and performed better examination for the improvement and better result. For apoptosis activity, we used annexin V parameter ; which is high level of annexin V indicates high apoptosis activity. In the result, it was shown that combination of melatonin and cisplatin groups in various concentration were better than cisplatin and melatonin alone ; (Annexin V level in C1 = 53.57 ; IC50 melatonin = 15.77 ; and cisplatin = 10.87). Thank you for the correction, it should be high e-cadherin level was associated with lower cell invasion and metastasis. I will correct it in the manuscript. For the 6 and 7 questions, I will gladly correct and add your revision in the manuscript. Thank you First of all, I am really grateful for the correction in this review, and also I would like to apologize for the late response This study was performed to prove that combination of melatonin and cisplatin in ovarian cancer had significant result in resistant ovarian cancer. We used SKOV 3 cell line which was ovarian cancer cell line that resemble with clear cell adenocarcinoma of ovary, this cell line was resistant to platinum chemotherapy such as cisplatin ; as we know that platinum group of chemotherapy is the first line in ovarian cancer treatment. Because of this, we only used SKOV 3 cell line (ATCC HTB-77) (cell that resistant to cisplatin treatment) and combination of melatonin and cisplatin to potentiate the effect in inhibition of the resistance. This might be good opportunity for other researcher to investigate and explore this research while using cell line that sensitive and resistant cell type, to improve the result. In this study, we compared the cisplatin, melatonin, and several combination of cisplatin and melatonin in various concentration, all of the result in this study shown that combination of cisplatin and melatonin in C1 group was superior than other combination groups; also with cisplatin and melatonin groups alone. In cell viability result, we would like to show that C1 group (37.57%) could reduce SKOV 3 cell viability which is why it was a good sign that combination of melatonin and cisplatin may inhibit the resistant ovarian cancer cell better than melatonin alone. The same result was also applied in C1 group of Pgp expression and GSH level compared to melatonin alone. The result was to show that combination of melatonin and cisplatin was better than melatonin, cisplatin, and doxorubicin alone. We used doxorubicin as the positive control, because doxorubicin act as second line drug of choice in platinum resistant ovarian cancer. We did not check the cell cycle activity because the aim of this study was to measure inhibition of resistant ovarian cancer cell using several parameters such as cell viability, CTR1, Pgp, GSH, ERCC1, e-cadherin, and Annexin V, because there was also limitation in funding. Further, for other researcher that interest with this study, may add the cell cycle and performed better examination for the improvement and better result. For apoptosis activity, we used annexin V parameter ; which is high level of annexin V indicates high apoptosis activity. In the result, it was shown that combination of melatonin and cisplatin groups in various concentration were better than cisplatin and melatonin alone ; (Annexin V level in C1 = 53.57 ; IC50 melatonin = 15.77 ; and cisplatin = 10.87). Thank you for the correction, it should be high e-cadherin level was associated with lower cell invasion and metastasis. I will correct it in the manuscript. For the 6 and 7 questions, I will gladly correct and add your revision in the manuscript. Thank you Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 21 Mar 2023 Views 0 Cite How to cite this report: Tortelli TC. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.142906.r188517 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v1#referee-response-188517 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 24 Jul 2023 Tharcisio C. Tortelli , Universidade de Sao Paulo, Sao Paulo, Brazil Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.142906.r188517 The article "Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer" provides evidences of a possible combination between cisplatin and melatonin to chemosensitize ovary cells to chemotherapy. However, the conclusion ... Continue reading READ ALL The article "Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer" provides evidences of a possible combination between cisplatin and melatonin to chemosensitize ovary cells to chemotherapy. However, the conclusion made by the authors cannot be made, as in any table, it is not shown if the cisplatin + melatonin combination is better than cisplatin or melatonin alone. This information is the most important because for a combination to work, it has to be better than its counterparts alone. The methodology used is not sufficient, as there is no point in using a fraction of the melatonin concentration if the result of the data analyzed is not shown with this fraction. As a result, C2, C3 and C4 groups are pointless to assume if the combination is better than the individual treatments alone. Also, using one cisplatin-resistant cell line is not sufficient. At least another one should be used. Another observations: Please, provide the results in graphics and not in table. It is better to be understood. The statement in the introduction "In addition, melatonin has a good effect on clinical outcomes in several cancers such as colon, breast, lung, and ovarian cancers" has no reference. Please, provide the result with the statistics of the MTS assay (table 2). Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? No Competing Interests: No competing interests were disclosed. Reviewer Expertise: Cell biology and develpment of new treatments for cancer therapy. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Tortelli TC. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.142906.r188517 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v1#referee-response-188517 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 18 Jun 2024 Cut Adeya Adella , Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia 18 Jun 2024 Author Response Thank you for the revision. This research was using several IC50 of melatonin and cisplatin combinations to show the effectiveness of melatonin and cisplatin combination concentration compared to IC50 melatonin-only, ... Continue reading Thank you for the revision. This research was using several IC50 of melatonin and cisplatin combinations to show the effectiveness of melatonin and cisplatin combination concentration compared to IC50 melatonin-only, which was the best combination form all of the combination groups. So, we made it in several combinations group. Also, we used cisplatin resistant type of cell line in this research because our purpose is to see the effectiveness of combination of melatonin and cisplatin on the inhibition of cisplatin resistant in ovarian cancer, maybe in the next research we will use other type of cell line for comparison. I have added the graphics in figure 3-8 of each markers to simplify the result, as it shown in the tables and figures, from MTS assay, it was shown that the combination group was better than melatonin-only group in reducing the cisplatin resistance, and for the result, it was explained before each of the tables and in discussion section that explain efficacy of combination group in each markers compared to melatonin-alone group. I have also added the reference in the statement. For table 2, we used MTS assay to see the percentage of viability cell by the value of it's abosrbancy, we performed it three times, and we got the mean value of absorbancy from the three performances of MTS assay, so the percentage of cell in table 2 was shown as the mean value of the absorbancy of MTS assay. I really appreciate your comments for the improvement in this article, thank you. Thank you for the revision. This research was using several IC50 of melatonin and cisplatin combinations to show the effectiveness of melatonin and cisplatin combination concentration compared to IC50 melatonin-only, which was the best combination form all of the combination groups. So, we made it in several combinations group. Also, we used cisplatin resistant type of cell line in this research because our purpose is to see the effectiveness of combination of melatonin and cisplatin on the inhibition of cisplatin resistant in ovarian cancer, maybe in the next research we will use other type of cell line for comparison. I have added the graphics in figure 3-8 of each markers to simplify the result, as it shown in the tables and figures, from MTS assay, it was shown that the combination group was better than melatonin-only group in reducing the cisplatin resistance, and for the result, it was explained before each of the tables and in discussion section that explain efficacy of combination group in each markers compared to melatonin-alone group. I have also added the reference in the statement. For table 2, we used MTS assay to see the percentage of viability cell by the value of it's abosrbancy, we performed it three times, and we got the mean value of absorbancy from the three performances of MTS assay, so the percentage of cell in table 2 was shown as the mean value of the absorbancy of MTS assay. I really appreciate your comments for the improvement in this article, thank you. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 18 Jun 2024 Cut Adeya Adella , Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia 18 Jun 2024 Author Response Thank you for the revision. This research was using several IC50 of melatonin and cisplatin combinations to show the effectiveness of melatonin and cisplatin combination concentration compared to IC50 melatonin-only, ... Continue reading Thank you for the revision. This research was using several IC50 of melatonin and cisplatin combinations to show the effectiveness of melatonin and cisplatin combination concentration compared to IC50 melatonin-only, which was the best combination form all of the combination groups. So, we made it in several combinations group. Also, we used cisplatin resistant type of cell line in this research because our purpose is to see the effectiveness of combination of melatonin and cisplatin on the inhibition of cisplatin resistant in ovarian cancer, maybe in the next research we will use other type of cell line for comparison. I have added the graphics in figure 3-8 of each markers to simplify the result, as it shown in the tables and figures, from MTS assay, it was shown that the combination group was better than melatonin-only group in reducing the cisplatin resistance, and for the result, it was explained before each of the tables and in discussion section that explain efficacy of combination group in each markers compared to melatonin-alone group. I have also added the reference in the statement. For table 2, we used MTS assay to see the percentage of viability cell by the value of it's abosrbancy, we performed it three times, and we got the mean value of absorbancy from the three performances of MTS assay, so the percentage of cell in table 2 was shown as the mean value of the absorbancy of MTS assay. I really appreciate your comments for the improvement in this article, thank you. Thank you for the revision. This research was using several IC50 of melatonin and cisplatin combinations to show the effectiveness of melatonin and cisplatin combination concentration compared to IC50 melatonin-only, which was the best combination form all of the combination groups. So, we made it in several combinations group. Also, we used cisplatin resistant type of cell line in this research because our purpose is to see the effectiveness of combination of melatonin and cisplatin on the inhibition of cisplatin resistant in ovarian cancer, maybe in the next research we will use other type of cell line for comparison. I have added the graphics in figure 3-8 of each markers to simplify the result, as it shown in the tables and figures, from MTS assay, it was shown that the combination group was better than melatonin-only group in reducing the cisplatin resistance, and for the result, it was explained before each of the tables and in discussion section that explain efficacy of combination group in each markers compared to melatonin-alone group. I have also added the reference in the statement. For table 2, we used MTS assay to see the percentage of viability cell by the value of it's abosrbancy, we performed it three times, and we got the mean value of absorbancy from the three performances of MTS assay, so the percentage of cell in table 2 was shown as the mean value of the absorbancy of MTS assay. I really appreciate your comments for the improvement in this article, thank you. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Mostafa Mir S. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.142906.r174251 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v1#referee-response-174251 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 19 Jun 2023 Seyed Mostafa Mir , Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Golestan Province, Iran Approved VIEWS 0 https://doi.org/10.5256/f1000research.142906.r174251 Congratulations on doing this wonderful research. The context was well written and the tables were informative. However; some changes can be done to improve this paper. The parts that need correction are highlighted in the PDF file , sincerely. ... Continue reading READ ALL Congratulations on doing this wonderful research. The context was well written and the tables were informative. However; some changes can be done to improve this paper. The parts that need correction are highlighted in the PDF file , sincerely. In the materials and sample size section, there is a writing mistake in the last sentence of paragraph 2. In the last sentence of Influx mechanism using CTR1 part, if the combination of cisplatin and melatonin has the higher rate of CTR1 expression so it should increase the drug influx not decrease it. As for the discussion section, the explanations were good enough however; I suggest you to use these articles to explain more about the melatonin and doxorubicin mechanisms and functions: - Melatonin: An anticancer molecule in esophageal squamous cell carcinoma: A mechanistic review 1 - Oncostatic activities of melatonin: Roles in cell cycle, apoptosis, and autophagy 2 - Melatonin: A smart molecule in the DNA repair system 3 - Melatonin and doxorubicin co-delivered via a functionalized graphene-dendrimeric system enhances apoptosis of osteosarcoma cells 4 These papers may help the writer to explain more about the mechanisms of melatonin. For example, in the introduction where the actions of melatonin are noted, these papers can help the writer to clarify the known mechanisms of melatonin by which it exerts oncostatic activities, regulatory actions on apoptosis, antiangiogenic actions, and etc. As for the discussion section, I suggest to explain more about the roles of melatonin in autophagy and chemotherapy adjuvant. Because of the main role of melatonin in this research, it would be better to elucidate the mechanisms of actions by which it exhibits anti-tumor effects, inhibits invasiveness, helps in DNA repair systems, and etc. Any of these mentioned references discusses these mechanisms and can be useful in order to improve the article. In the Conclusion section, the increase in E-Cadherin expression in C1 group should decrease the EMT process and thus leads to a decrease in drug resistance. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes References 1. Heydari N, Memar M, Reiter R, Rezatabar S, et al.: Melatonin: An anticancer molecule in esophageal squamous cell carcinoma: A mechanistic review. Melatonin Research . 2023; 6 (1): 59-71 Publisher Full Text 2. Targhazeh N, Reiter RJ, Rahimi M, Qujeq D, et al.: Oncostatic activities of melatonin: Roles in cell cycle, apoptosis, and autophagy. Biochimie . 2022; 200 : 44-59 PubMed Abstract | Publisher Full Text 3. Mir SM, Aliarab A, Goodarzi G, Shirzad M, et al.: Melatonin: A smart molecule in the DNA repair system. Cell Biochem Funct . 2022; 40 (1): 4-16 PubMed Abstract | Publisher Full Text 4. Niu G, Yousefi B, Qujeq D, Marjani A, et al.: Melatonin and doxorubicin co-delivered via a functionalized graphene-dendrimeric system enhances apoptosis of osteosarcoma cells. Mater Sci Eng C Mater Biol Appl . 2021; 119 : 111554 PubMed Abstract | Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Cancer research and melatonin I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Mostafa Mir S. Reviewer Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.142906.r174251 ) The direct URL for this report is: https://f1000research.com/articles/12-313/v1#referee-response-174251 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 28 Jul 2023 Cut Adeya Adella , Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia 28 Jul 2023 Author Response Thank you for the correction to improve this paper and also for the response. Competing Interests: No competing interests were disclosed. Thank you for the correction to improve this paper and also for the response. Thank you for the correction to improve this paper and also for the response. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 28 Jul 2023 Cut Adeya Adella , Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia 28 Jul 2023 Author Response Thank you for the correction to improve this paper and also for the response. Competing Interests: No competing interests were disclosed. Thank you for the correction to improve this paper and also for the response. Thank you for the correction to improve this paper and also for the response. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 4 VERSION 4 PUBLISHED 21 Mar 2023 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 4 5 6 7 Version 4 (revision) 06 Jun 25 read read read read read Version 3 (revision) 02 Sep 24 read read Version 2 (revision) 12 Feb 24 read Version 1 21 Mar 23 read read Seyed Mostafa Mir , Golestan University of Medical Sciences, Gorgan, Iran Tharcisio C. Tortelli , Universidade de Sao Paulo, Sao Paulo, Brazil Pavel Souček , Charles University, Pilsen, Czech Republic Karin Rodland , Oregon Health & Science University, Portland, USA Jan Brancewicz , Cellis, Warsaw, Poland Cansu Umran TUNC , The University of Utah, Salt Lake City, USA Mara Artibani , University of Oxford, Oxford, UK Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Artibani M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 27 Dec 2025 | for Version 4 Mara Artibani , University of Oxford, Oxford, UK 0 Views copyright © 2025 Artibani M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The manuscript examines the effects of melatonin combined with cisplatin in SKOV3 ovarian cancer cells. While the topic is relevant, the study suffers from conceptual, methodological, statistical, and linguistic flaws that prevent any meaningful scientific conclusions. Several issues highlighted by previous reviewers remain unresolved. Major Concerns 1. Inappropriate cell model The authors repeatedly claim to investigate “cisplatin resistance,” yet the only model used is SKOV3 , which is not a cisplatin-resistant ovarian cancer cell line. Resistance is never demonstrated experimentally, nor are resistant vs sensitive models compared. 2. Experimental design cannot test resistance Melatonin and cisplatin were added simultaneously for 48 hours. This measures acute cytotoxicity only. It does not model: acquired resistance intrinsic resistance reversal or inhibition of resistance 3. Misuse and misunderstanding of IC50 Terms such as “1× IC50,” “¾× IC50,” etc. are used as if IC50 were a standardized dose unit, rather than a calculated concentration. This is conceptually incorrect. The combination dosing strategy is unjustified and difficult to interpret. 4. Lack of mechanistic evidence Although the Discussion lists numerous pathways (AKT, JNK, MMP-9, NF-κB, BAX/BCL-2, etc.), none are evaluated experimentally. The only measurements made are: CTR1, Pgp, GSH, ERCC1, E-cadherin, Annexin V. All via single-parameter flow cytometry, without orthogonal validation (e.g., Western blots). This is insufficient to support mechanistic claims. 6. Statistical and interpretive errors In key comparisons (e.g., Pgp, GSH), the combination (C1) is not significantly different from melatonin alone. Yet the manuscript claims the combination “reduces efflux” or “reduces drug inactivation.” This is incorrect: in several cases, melatonin alone accounts for the effect. Additionally, many effect sizes are small and likely not biologically meaningful. 7. Methodological problems No explanation of flow cytometry gating, live/dead exclusion, or compensation. No validation of antibody specificity. Critical details omitted; trivial procedural steps over-described. Disturbing methodological phrasing (e.g., implying 70% ethanol was present in culture flasks) suggests poor proofreading or conceptual errors. 8. Writing quality and use of scientific language The manuscript exhibits extensive issues: Frequent grammatical errors (e.g., “it’s” vs “its”). Non-standard terminology (“variables” for treatments, “laboratory experiment”). Inconsistent units (mM vs μM). Unclear or awkward phrasing. Overly long explanations of irrelevant details and insufficient explanation of essential methods. 9. Overstated conclusions The manuscript concludes that melatonin “reduces chemoresistance” and modulates multiple resistance pathways. Given the inappropriate model, flawed design, and weak data, these statements are unsupported and should not be made. Minor Concerns Figures lack two-parameter cytometry plots. The Limitations section remains incomplete despite revisions. The Discussion is overly long and contains speculative content not grounded in the study's findings. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? No Competing Interests No competing interests were disclosed. Reviewer Expertise Ovarian cancer I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Artibani M. Peer Review Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r429767) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-429767 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Umran TUNC C. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 11 Dec 2025 | for Version 4 Cansu Umran TUNC , The University of Utah, Salt Lake City, Utah, USA 0 Views copyright © 2025 Umran TUNC C. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The paper discusses the potential effect of the combination of melatonin and cisplatin treatment on cisplatin resistance in ovarian cancer. The study presents data on viability and potential drug resistance pathways. It gives some insights into the combination therapy. However, the paper is poorly written. The introduction is insufficient to explain the hypothesis, aims, and outcomes of the study. The results were not discussed at all. The experimental design should include a drug-resistant cell line to draw a conclusion. The protein analysis did not reveal any significant differences between the combination groups and single treatment groups. The authors should calculate the combination index using an appropriate method to understand whether the effect is additive, combinatorial, or antagonistic. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Drug delivery, gene therapy, combination drug therapy, and molecular biology I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Umran TUNC C. Peer Review Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r427782) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-427782 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Brancewicz J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 08 Dec 2025 | for Version 4 Jan Brancewicz , Cellis R&D, Cellis, Warsaw, Poland 0 Views copyright © 2025 Brancewicz J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Dear Authors, Thank you for your submission. While your topic is of potential interest, the manuscript requires substantial revision in study design, methodological accuracy, data presentation, figure quality, and English usage. Please find my detailed comments below, organized according to the structure of your manuscript. General Evaluation The overall presentation of this work remains scientifically immature. Data visualization is the main weakness: results are presented in raw tables that are difficult to interpret, with statistical outcomes detached from figures and not shown graphically. The study relies on a single cell line (SKOV-3), which makes the conclusions unreliable and not generalizable to ovarian cancer biology. Methodological details are incomplete, and flow cytometry protocols deviate from accepted standards, affecting reproducibility. Furthermore, the discussion is mostly a literature summary and fails to contextualize or critically interpret the presented data. Finally, the English language requires extensive professional revision to correct grammar, syntax, and terminology, avoiding both colloquial expressions (“each cell was exposed to each material”) and inconsistent scientific notation (“ethanol 70%,” “5% CO2,” “tripsin,” etc.). Section-by-Section Comments Introduction (Page 3) – Grammar: “modulates” instead of “modulate.” – “Melatonin has a good effect on clinical outcomes…” - this statement requires a supporting reference. – The text contains redundant and stylistically awkward phrasing; revise for clarity and conciseness. – The introduction should better define the rationale of using melatonin with cisplatin in cisplatin-resistant ovarian cancer and explicitly describe the hypothesis tested. Materials and Methods (Pages 4–6) General remarks – The description of the experimental workflow is confusing and sometimes inaccurate. Please clearly separate (i) cell culture maintenance, (ii) treatment scheme, (iii) IC50 determination, and (iv) flow cytometry analyses. – Provide complete details to ensure reproducibility: antibody clones, fluorophores, concentrations/dilutions, solvents, manufacturers, and whether compensation was applied. – Replace rpm values with relative centrifugal force (× g) or provide rotor radius. – Use correct scientific notation and proper typographical style (e.g., 70% ethanol, 5% CO₂, 37 °C). – Institutions where experiments were performed should be mentioned in Acknowledgements, not in Methods. Delete time information as well. Specific remarks – Page 4, paragraph 1: Correct “tripsin” to “trypsin.” – Page 4, line 5: Remove redundant mention of experiment dates and locations; cite only ethical approval code. – Page 4, “IC50 determination”: “Solutions” of what? Please specify whether these refer to drug dilutions or stock solutions. – Indicate the number of biological replicates (n) per group and the number of technical replicates per assay. – “GraphPad software was used to analyze the IC50 values.” - Specify which version, which regression model, and statistical parameters (e.g., non-linear fit, R²). – Describe the criteria for IC50 derivation (interpolation, nonlinear regression, etc.). – Provide justification for the concentration ranges used. – Page 5, “Cytotoxic activity”: a) Replace colloquial “each cell was exposed to each material” with “each cell line was treated with reagents as described in Table 1.” b) Use “Gibco” instead of “Gibsco.” c) Replace “ethanol 70%” with “70% ethanol.” d) Replace “the solution was read” with “absorbance was measured.” e) The explanation of MTS assay principle is unnecessary and may be removed. – Page 5, “Preparation of cell for flow cytometry”: rename to “Preparation of samples for flow cytometry.” – Clarify the exact buffer composition and manufacturer (e.g., “stain buffer (BD Biosciences, Cat. no. 554656)”). – Page 5–6, “Flow cytometry of CTR-1 and P-gp / GSH / ERCC1 / E-cadherin / Annexin V”: a) The use of room-temperature or 37 °C antibody incubation is non-canonical and introduces non-specific binding. These steps must be performed on ice (4 °C). b) State explicitly whether cells were live-stained or fixed/permeabilized; name the fixation buffer (e.g., “Cytofix/Cytoperm, BD Biosciences”) and manufacturer. c) Define whether values represent percentages of marker-positive live cells or total events. d) Indicate gating strategy, compensation controls, and whether isotype controls were used. e) Clarify the meaning of “permwash buffer”; give manufacturer and catalog number. f) Provide antibody clones, conjugates, and catalog numbers for all targets (CTR-1, P-gp, GSH, ERCC-1, E-cadherin, Annexin V). – Page 6, “Statistical analysis”: a) Describe tests for normality and variance (e.g., Shapiro-Wilk, Levene’s). b) State whether p-values were two-tailed and corrected for multiple comparisons. c) Define how data are expressed (mean ± SD or SEM). d) Specify software precisely: “SPSS v21.0 (IBM, Armonk, NY, USA).” e) Add sample sizes (n) for each group. Results (Pages 6–11) – The section begins redundantly (“In this study, SKOV3 cells were used.”); delete this sentence. – Authors used only one cell line (SKOV-3) whereas they should consider using the panel of 4-5 of them (e.g. ATCC TCP-1021 and OVCAR-4), some of which are cisplatin resistant, and some which are cisplatin sensitive. – Photographs in Figures 1–2 are of poor quality and must be replaced with high-resolution micrographs. – Merge Figures 1 and 2, as they both present microscopy. – Table 1 lacks consistency with text (C1–C4 naming); unify across manuscript. – Change “Cell culture was observed” to “Cells were photographed.” – Tables 2–8 should be replaced with graphs showing mean ± SD, n, and statistical annotations (stars or symbols). – Clarify whether data represent percentages of marker-positive cells or mean fluorescence intensities (MFI). – Always specify: (i) test used, (ii) n biological replicates, (iii) n technical replicates, (iv) type of error bars, (v) reference group for significance. – Table 2 – Add SD/SE; explain “Medium control 0%” and number of replicates. – Tables 3–8 – Provide SD/SE values and make sure all statistical comparisons correspond to figure symbols. – CTR1 section: Authors should also compare C1 vs C4 groups; currently only comparisons vs single agents are shown. – P-gp section: The “IC Doxorubicin” group cannot realistically have 0.0 % P-gp expression if viability > 0; add FMO control and address this inconsistency. – Throughout Results, avoid imprecise language such as “chemotherapy influx” - refer to specific drug (cisplatin or doxorubicin). – Replace “dry” tables with summarized figures and combine all data (Tables 2–8) into a single multi-panel figure for clarity. Discussion (Pages 12–14) – The first paragraph repeats sentences verbatim: “Melatonin exhibits anti-inflammatory, anti-tumor, and anti-proliferative activities…” - delete duplication. – Add reference supporting the claim that melatonin has “minimal side effects.” – The term “single-use therapy” is non-scientific and should be replaced with “monotherapy.” – The Discussion merely lists literature facts about CTR1, P-gp, GSH, etc., but does not confront them with your own results. Revise to discuss how your findings agree or conflict with prior studies. – Clarify what is novel in your dataset relative to the cited works. – Avoid repeating descriptions of published mechanisms without connecting them to your data. – Extend the section summarizing limitations (cell-line restriction, lack of validation, non-orthogonal confirmation of flow cytometry by Western blot, etc.) - this is essential for transparency and scientific maturity. Conclusion (Page 14) – The conclusions are generally aligned with the data shown but overstate the certainty of findings. – Emphasize that results are preliminary and limited to one cell line; avoid causal language (“may reduce chemoresistance” instead of “reduce”). – Indicate that further validation using additional cell lines and in vivo studies is required. Data Availability and References – Ensure all Mendeley, protocols.io and DOI links are functional. – Clearly describe the content of each dataset (raw .csv files, flow cytometry .fcs files, microscopy .tif images). – Unify reference style (PubMed/DOI consistency). – Verify that all statements in the text are properly referenced. Language and Formatting Issues The manuscript contains numerous grammatical and stylistic errors, including: – “cell was centrifuged” → “cells were centrifuged” (repeated error throughout) – “in each cell” → “in each cell line” – “cell solution” instead of “cell suspension” – Replace “flowcytometry” with “flow cytometry” everywhere. – Maintain consistent tense (past for Methods, present for Results/Discussion). A thorough language edit by a native or professional scientific editor is mandatory before resubmission. Overall Assessment The study’s premise is potentially interesting, but methodological rigor, data visualization, and clarity fall short of scientific standards. The use of only one cell line, incomplete methodological information, non-standard flow cytometry protocols, and poor figure quality severely limit reproducibility and interpretation. The Discussion must be rewritten to critically evaluate the results against existing literature. Until these issues are comprehensively addressed, the manuscript cannot be recommended for indexing. Best regards, Jan Brancewicz Is the work clearly and accurately presented and does it cite the current literature? No Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? No If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? No Competing Interests No competing interests were disclosed. Reviewer Expertise My research focuses on cell biology and translational medicine, combining wet-lab experimental work with quantitative data analysis. I study the interactions between immune cells and cancer, particularly macrophage-based therapies for solid tumors, integrating molecular and cellular assays, microscopy, and statistical evaluation of preclinical data to support the development of innovative therapeutic approaches. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Brancewicz J. Peer Review Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r429776) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-429776 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Rodland K. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 09 Aug 2025 | for Version 4 Karin Rodland , Oregon Health & Science University, Portland, Oregon, USA 0 Views copyright © 2025 Rodland K. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The manuscript ‘Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer’, has made the interesting observation that treating SKOV3 cells with combinations of millimolar melatonin and micromolar cisplatin resulted in decreased cell viability and increased apoptosis compared to either agent alone. However, despite several rounds of revision, the manuscript is still significantly flawed and has failed to address the most serious concerns expressed in prior reviews. First, the use of a single cell line, SKOV3, is essentially a fatal flaw which cannot be adequately dealt with simply by acknowledging that it would be better to use more cell lines. One simply cannot say anything about the effects of melatonin on cisplatin resistance without comparing sensitive and resistance cell populations. As the researchers had the resources to do multiple replicates of the experiment, per the text, and include partial combinations of cisplatin and melatonin that are difficult to defend logically, it should have been possible to perform the key experiments on at least a second cell line. The fundamental design of the experiments also brings up another problem. By adding melatonin and cisplatin concurrently, and harvesting the cells 48 hours later, it is unclear whether the authors are proposing that melatonin will delay the development of platinum resistance or provide an alternative mechanism for cell death in cells that are already cisplatin resistant. This is a crucial question in the context of potential clinical relevance, which appears to be the justification for these experiments based on the abstract and introduction. If the concept is to treat ovarian cancers that are known to be platinum resistant or refractory, then the data presented clearly show that melatonin, alone or in conjunction with cisplatin, is substantially inferior to doxorubicin alone, a clinically tested and approved second line therapy for platinum resistant ovarian cancer. The third problem is that we learn nothing about the mechanisms of action of melatonin, alone or in conjunction with cisplatin, from these experiments. The decision to measure CTR1, Pgp, and GSH implies the hypothesis that melatonin has the potential to act via traditional mechanisms of drug influx, efflux, and/or inactivation, but in all these experiments there is no statistically significant difference between melatonin alone and melatonin + cisplatin; therefore, hypotheses related to drug metabolism are disproven, but that is never discussed. In response to prior reviews, the authors have increased their citations relating to actions of melatonin in other systems, including the naming of cellular pathways shown to be modulated in other publications, but there is no attempt to measure any of these endpoints in their experimental system. This is a major limitation of the choice of flow cytometry as the primary measurement platform. Had the authors chosen to prepare Western blots, the same membrane could have been probed with a large number of antibodies to establish possible changes in MMP-9, AKT, JNK1/2, ERK1/2, and other potential pathways. Annexin-V and E-cadherin could have been easily measured in Western blots, providing orthogonal validation of the flow cytometry results. Minor errors in the manuscript include: Identification of SKOV3 as a clear cell ovarian cancer when it is a serious adenocarcinoma The abstract uses mM to define the IC50 for melatonin, cisplatin, and doxorubicin, whereas the text gives the IC50 for cisplatin and doxorubicin in uM. If the IC50s are truly in mM, then the use of 4 significant figures for melatonin is inappropriate. Most analytical chemists would like to see justification for 4 significant figures, given that the doses administered were only accurate to 2 significant figures. Since all of the quantification was given as ‘per cent labeled cells’ by flow cytometry, the Methods section needs to be absolutely clear that this is ‘per centage of live cells’, as including dead cells in the analysis could have biased the results, given the differences in cell viability Again, given that all protein measurements were made by flow cytometry, it would have been nice to see two-axis flow diagrams, at the very least for ERCC1 and E-cadherin, which were apparently measured simultaneously. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise cancer cell biology, specifically ovarian and breast cancers; cancer proteogenomics; cancer biomarkers I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Rodland K. Peer Review Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r396249) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-396249 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Tortelli T. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 25 Jun 2025 | for Version 4 Tharcisio C. Tortelli , Universidade de Sao Paulo, Sao Paulo, Brazil 0 Views copyright © 2025 Tortelli T. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Thank you for the answers but some of the problems remains. Some of the conclusions like P-glycoprotein expression and GSH level have no correspond in the results because the melatonin IC50 is equal to the combination of CIS + melatonin. The result show that is pointless to add cisplatin in these cases. Also, by using one cell line, being cisplatin-resistant or not, the author cannot generalize the results to ovarian cancer. This is a huge step. Competing Interests No competing interests were disclosed. Reviewer Expertise Cell biology and develpment of new treatments for cancer therapy. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Tortelli TC. Peer Review Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.183324.r390100) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-313/v4#referee-response-390100 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Souček P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 11 Sep 2024 | for Version 3 Pavel Souček , Charles University, Pilsen, Czech Republic 0 Views copyright © 2024 Souček P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (2) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors reflected some of my criticisms. On the other hand, the most serious concerns remain unresolved. I understand that adding another cell line would substantially shift the paper indexing period. However, at least a statement that the results need verification using other cell lines should be placed in the Discussion under the study limitations section. This section is actually missing and should be included. Additionally, the fact that I have pointed out, i.e. that the observed changes between treatments are too small to be biologically relevant was left unattended. Again, to make this report more plausible, the statement that observations are just indicative or hypothesis-generating and have to be confirmed by many additional studies has to be added to the above-mentioned study limitations. The authors should frankly list such studies, i.e. search for conditions giving more robust differences, defining the relevant mechanism behind them (because the list of all pathways in the Conclusion is hardly acceptable - some can be drivers and other just consequences), and finally confirmation by in vivo experiment where the bioavailability of dosing should also be tested. The Discussion section should be reconstructed accordingly. Competing Interests No competing interests were disclosed. Reviewer Expertise cancer biology I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (2) Author Response 17 Sep 2024 Cut Adeya Adella, Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia Thank you for the suggestion, may i ask - should i also add the bioavailability of dosing that should also be tested by in vivo and confirm it in the limitations ? - what else in the discussion site that should be reconstructed so i can make all of the suggestions included in the revision ? Thank you View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Author Response 11 Aug 2025 Cut Adeya Adella, Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia Thank you for the comment and correction, i also apologize for the late respond of your revision. I have added the limitation section in the new correction. It is important to show that this study need to be expanded and developed so it can show the melatonin effect on other cell line. I have added the statement this result may need to other study to confirm and verificate the effect of melatonin on other cell line. I have also added the statement that the statement that observations are just indicative or hypothesis-generating and have to be confirmed by many additional studies and statement that it must be performed in vivo to see the bioavailability of dosing in limitation section. The conclusion section have been corrected. I have added several studies that explain melatonin mechanism in chemoresistance in the discussion section and corrected the conclusion section. Once again, i greatly appreciate the suggestion and look forward for your comment View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Souček P. Peer Review Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.171173.r319904) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-313/v3#referee-response-319904 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Tortelli T. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 04 Sep 2024 | for Version 3 Tharcisio C. Tortelli , Universidade de Sao Paulo, Sao Paulo, Brazil 0 Views copyright © 2024 Tortelli T. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Thank you for the answers. The conclusion is wrong for some of the results. For PGP expression, the authors cannot say that the combination works because there is no statistical difference between C1 group and IC50mel. This way, why adding cisplatin? The effect observed is due to melatonin only. The same conclusion works for GSH where again, there is no statistical difference between C1 group and IC50mel. The point of my first review is that the combination must be better than cisplatin and melatonin treatment alone. Any other situation shows that the combination is not necessary because there was no improvement when adding the other drug. The conclusion is too strong for the results. Despite the use of the term “may”, it is too early to assume anything because there is no functional assay. Also, the conclusion is too generic as the experiments were done in just one cell line. Competing Interests No competing interests were disclosed. Reviewer Expertise Cell biology and develpment of new treatments for cancer therapy. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 10 Sep 2025 Cut Adeya Adella, Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia First of all, i apologize for the late respond of your comment. I appreciate your correction. P glycoprotein is a transmembrane glycoprotein as an efflux transporter specifically for chemotherapy. Higher PgP percentage indicates that cytotoxic agent is inhibited to entry into the cell and may reduce the effect of chemotherapy in cancer cell, so the resistance is high. In this result, it was shown from the Bonferroni test, between IC50 melatonin and Pgp also IC50 melatonin and GSH, there were statistically no difference. We performed the Bonferroni to show which pair variables have significantly different. The main purpose of this research was to shown that C1 group (combination of 1x IC50 melatonin and 1x IC50 cisplatin) was better than IC50 cisplatin alone, and from the result there was significant different in each markers of ovarian resistance. I have included the explanation about those that were no difference in the result part. Because we performed it in SKOV 3 in this first experiment in cisplatin resistance ovarian cancer, in the next research it would be better to use this combination in other ovarian cancer cell line that resistant to cisplatin. I have added the suggestion in the conclusion part. Thank you for the suggestion and correction. I look forward for your comment. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Tortelli TC. Peer Review Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.171173.r319902) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-313/v3#referee-response-319902 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Souček P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 27 Jun 2024 | for Version 2 Pavel Souček , Charles University, Pilsen, Czech Republic 0 Views copyright © 2024 Souček P. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors of the paper Cut Adeya Adella et al. report the results of an in vitro study of a combination regimen composed of cisplatin and melatonin in an ovarian cancer SKOV3 cell line model. They conclude that the combination of melatonin with cisplatin at a dose close to IC 50 decreases cell viability, increases protein expression of influx transporter CTR1, and reduces that of efflux p-glycoprotein. Other markers changed by this combination include a reduced GSH level and ERCC1 protein expression. The observed increase of E-cadherin expression suggested a potential slowdown of epithelial-mesenchymal transition, and annexin V staining points to stimulation of apoptosis. The findings, if confirmed by independent studies and different approaches, can be interesting for the next phase of preclinical research in this area. The content of the paper suits well to the scope of the F1000 journal. Major criticisms 1/ Although potentially interesting and important, the results rely on findings made only using one cell line, which does not robustly represent ovarian cancer. Experiments on two or three cell lines are recommended for in vitro studies. Also, the claim that SKOV3 represents resistant ovarian cancer is not enough. Optimally, experiments on sensitive and resistant subclones of the same cell line would be needed to show some differences and specificity of observed effects for resistant models. 2/ The data in Table 2 show that the effect of combinations on cell viability is very mild – between 37.6 and 48.4% compared to 47.7% for melatonin and 55.2% for cisplatin alone. How biologically relevant is such synergy? The same applies to the C1 combination regarding PgP expression (Table 4) and GSH level (Table 5), which are not much different from melatonin alone. 3/ Why doxorubicin was used as “positive control”? This drug is not used in ovarian cancer treatment at all. Mechanisms of action are completely different from platinum derivatives. 4/ Why cell cycle was not followed? The rest of the experiments were done by flow cytometry anyway, and melatonin or cisplatin did not cause much apoptosis. 5/ The Discussion section contains several controversial statements, e.g., “High e-cadherin was associated with high activities of invasive cancer and metastasis (Loh et al., 2019).“ Further: “Melatonin administration increased e-cadherin expression... Melatonin may decrease the migration and invasion activities of cancer cells (Goncalves et al., 2016).“ Moreover, in the present study, C1 increased E-cadherin over cisplatin or melatonin alone (Fig. 7). So, is high E-cadherin good or bad for eventual patients? Overall, the discussion would profit from the scheme of the main effect or mechanism behind the C1 combination. Minor comments 6/ Statistical tests should be described in Methods. 7/ GSH should be referred to as peptide, and terms level or concentration better reflect its amount than “expression”. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise cancer biology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 29 Aug 2024 Cut Adeya Adella, Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia First of all, I am really grateful for the correction in this review, and also I would like to apologize for the late response This study was performed to prove that combination of melatonin and cisplatin in ovarian cancer had significant result in resistant ovarian cancer. We used SKOV 3 cell line which was ovarian cancer cell line that resemble with clear cell adenocarcinoma of ovary, this cell line was resistant to platinum chemotherapy such as cisplatin ; as we know that platinum group of chemotherapy is the first line in ovarian cancer treatment. Because of this, we only used SKOV 3 cell line (ATCC HTB-77) (cell that resistant to cisplatin treatment) and combination of melatonin and cisplatin to potentiate the effect in inhibition of the resistance. This might be good opportunity for other researcher to investigate and explore this research while using cell line that sensitive and resistant cell type, to improve the result. In this study, we compared the cisplatin, melatonin, and several combination of cisplatin and melatonin in various concentration, all of the result in this study shown that combination of cisplatin and melatonin in C1 group was superior than other combination groups; also with cisplatin and melatonin groups alone. In cell viability result, we would like to show that C1 group (37.57%) could reduce SKOV 3 cell viability which is why it was a good sign that combination of melatonin and cisplatin may inhibit the resistant ovarian cancer cell better than melatonin alone. The same result was also applied in C1 group of Pgp expression and GSH level compared to melatonin alone. The result was to show that combination of melatonin and cisplatin was better than melatonin, cisplatin, and doxorubicin alone. We used doxorubicin as the positive control, because doxorubicin act as second line drug of choice in platinum resistant ovarian cancer. We did not check the cell cycle activity because the aim of this study was to measure inhibition of resistant ovarian cancer cell using several parameters such as cell viability, CTR1, Pgp, GSH, ERCC1, e-cadherin, and Annexin V, because there was also limitation in funding. Further, for other researcher that interest with this study, may add the cell cycle and performed better examination for the improvement and better result. For apoptosis activity, we used annexin V parameter ; which is high level of annexin V indicates high apoptosis activity. In the result, it was shown that combination of melatonin and cisplatin groups in various concentration were better than cisplatin and melatonin alone ; (Annexin V level in C1 = 53.57 ; IC50 melatonin = 15.77 ; and cisplatin = 10.87). Thank you for the correction, it should be high e-cadherin level was associated with lower cell invasion and metastasis. I will correct it in the manuscript. For the 6 and 7 questions, I will gladly correct and add your revision in the manuscript. Thank you View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Souček P. Peer Review Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.160652.r291392) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-313/v2#referee-response-291392 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2023 Tortelli T. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 24 Jul 2023 | for Version 1 Tharcisio C. Tortelli , Universidade de Sao Paulo, Sao Paulo, Brazil 0 Views copyright © 2023 Tortelli T. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The article "Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer" provides evidences of a possible combination between cisplatin and melatonin to chemosensitize ovary cells to chemotherapy. However, the conclusion made by the authors cannot be made, as in any table, it is not shown if the cisplatin + melatonin combination is better than cisplatin or melatonin alone. This information is the most important because for a combination to work, it has to be better than its counterparts alone. The methodology used is not sufficient, as there is no point in using a fraction of the melatonin concentration if the result of the data analyzed is not shown with this fraction. As a result, C2, C3 and C4 groups are pointless to assume if the combination is better than the individual treatments alone. Also, using one cisplatin-resistant cell line is not sufficient. At least another one should be used. Another observations: Please, provide the results in graphics and not in table. It is better to be understood. The statement in the introduction "In addition, melatonin has a good effect on clinical outcomes in several cancers such as colon, breast, lung, and ovarian cancers" has no reference. Please, provide the result with the statistics of the MTS assay (table 2). Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? No Competing Interests No competing interests were disclosed. Reviewer Expertise Cell biology and develpment of new treatments for cancer therapy. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 18 Jun 2024 Cut Adeya Adella, Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia Thank you for the revision. This research was using several IC50 of melatonin and cisplatin combinations to show the effectiveness of melatonin and cisplatin combination concentration compared to IC50 melatonin-only, which was the best combination form all of the combination groups. So, we made it in several combinations group. Also, we used cisplatin resistant type of cell line in this research because our purpose is to see the effectiveness of combination of melatonin and cisplatin on the inhibition of cisplatin resistant in ovarian cancer, maybe in the next research we will use other type of cell line for comparison. I have added the graphics in figure 3-8 of each markers to simplify the result, as it shown in the tables and figures, from MTS assay, it was shown that the combination group was better than melatonin-only group in reducing the cisplatin resistance, and for the result, it was explained before each of the tables and in discussion section that explain efficacy of combination group in each markers compared to melatonin-alone group. I have also added the reference in the statement. For table 2, we used MTS assay to see the percentage of viability cell by the value of it's abosrbancy, we performed it three times, and we got the mean value of absorbancy from the three performances of MTS assay, so the percentage of cell in table 2 was shown as the mean value of the absorbancy of MTS assay. I really appreciate your comments for the improvement in this article, thank you. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Tortelli TC. Peer Review Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.142906.r188517) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-313/v1#referee-response-188517 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2023 Mostafa Mir S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 19 Jun 2023 | for Version 1 Seyed Mostafa Mir , Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Golestan Province, Iran 0 Views copyright © 2023 Mostafa Mir S. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Congratulations on doing this wonderful research. The context was well written and the tables were informative. However; some changes can be done to improve this paper. The parts that need correction are highlighted in the PDF file , sincerely. In the materials and sample size section, there is a writing mistake in the last sentence of paragraph 2. In the last sentence of Influx mechanism using CTR1 part, if the combination of cisplatin and melatonin has the higher rate of CTR1 expression so it should increase the drug influx not decrease it. As for the discussion section, the explanations were good enough however; I suggest you to use these articles to explain more about the melatonin and doxorubicin mechanisms and functions: - Melatonin: An anticancer molecule in esophageal squamous cell carcinoma: A mechanistic review 1 - Oncostatic activities of melatonin: Roles in cell cycle, apoptosis, and autophagy 2 - Melatonin: A smart molecule in the DNA repair system 3 - Melatonin and doxorubicin co-delivered via a functionalized graphene-dendrimeric system enhances apoptosis of osteosarcoma cells 4 These papers may help the writer to explain more about the mechanisms of melatonin. For example, in the introduction where the actions of melatonin are noted, these papers can help the writer to clarify the known mechanisms of melatonin by which it exerts oncostatic activities, regulatory actions on apoptosis, antiangiogenic actions, and etc. As for the discussion section, I suggest to explain more about the roles of melatonin in autophagy and chemotherapy adjuvant. Because of the main role of melatonin in this research, it would be better to elucidate the mechanisms of actions by which it exhibits anti-tumor effects, inhibits invasiveness, helps in DNA repair systems, and etc. Any of these mentioned references discusses these mechanisms and can be useful in order to improve the article. In the Conclusion section, the increase in E-Cadherin expression in C1 group should decrease the EMT process and thus leads to a decrease in drug resistance. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes References 1. Heydari N, Memar M, Reiter R, Rezatabar S, et al.: Melatonin: An anticancer molecule in esophageal squamous cell carcinoma: A mechanistic review. Melatonin Research . 2023; 6 (1): 59-71 Publisher Full Text 2. Targhazeh N, Reiter RJ, Rahimi M, Qujeq D, et al.: Oncostatic activities of melatonin: Roles in cell cycle, apoptosis, and autophagy. Biochimie . 2022; 200 : 44-59 PubMed Abstract | Publisher Full Text 3. Mir SM, Aliarab A, Goodarzi G, Shirzad M, et al.: Melatonin: A smart molecule in the DNA repair system. Cell Biochem Funct . 2022; 40 (1): 4-16 PubMed Abstract | Publisher Full Text 4. Niu G, Yousefi B, Qujeq D, Marjani A, et al.: Melatonin and doxorubicin co-delivered via a functionalized graphene-dendrimeric system enhances apoptosis of osteosarcoma cells. Mater Sci Eng C Mater Biol Appl . 2021; 119 : 111554 PubMed Abstract | Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Cancer research and melatonin I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (1) Author Response 28 Jul 2023 Cut Adeya Adella, Obstetric and Gynecology Department, Gynecology Oncology Division, Medical Faculty, Universitas Sumatera Utara, Medan, 20155, Indonesia Thank you for the correction to improve this paper and also for the response. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Mostafa Mir S. Peer Review Report For: Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer [version 4; peer review: 1 approved, 6 not approved] . F1000Research 2025, 12 :313 ( https://doi.org/10.5256/f1000research.142906.r174251) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-313/v1#referee-response-174251 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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