Curcumin's Therapeutic Potential in Ovarian Cancer: Current Insights and Future Perspectives.

Smirnova Elena: conceptualization (lead), writing – original draft (lead), writing – review and editing (lead). Sureshbabu Anjana: writing – review and editing (supporting). Do Thi Cat Tuong: writing – review and editing (supporting). Sungyeon Chin: writing – review and editing (supporting). Mohammad Moniruzzaman: writing – review and editing (supporting). Bui Huy Doanh: writing – review and editing (supporting). Adhimoolam Karthikeyan: conceptualization (equal), project administration (equal), supervision (equal), writing – review and editing (supporting). Taesun Min: conceptualization (equal), funding acquisition (equal), project administration (equal), writing – review and editing (supporting).

The authors have nothing to report.

Ovarian cancers are categorized into three main types: epithelial ovarian carcinomas, germ cell tumors, and stromal cell tumors. Epithelial ovarian carcinomas—accounting for approximately 85%–90% of all cases, originate from the ovarian surface cells. This category includes several histological subtypes, such as serous, endometrioid, clear cell, mucinous, and undifferentiated variants. Germ cell tumors, which account for less than 2% of ovarian cancers, primarily affect younger individuals, and are associated with a 5‐year survival rate of approximately 90%. Stromal cell tumors, comprising about 1% of cases, originate in the ovarian supportive tissues. They are often detected at an early stage and commonly present with symptoms such as abnormal vaginal bleeding (Gaona‐Luviano et al.  2020 ). Detecting early‐stage ovarian cancer remains a challenge due to its subtle, nonspecific symptoms, which include abdominal bloating, rapid satiety, and increased urination (Orr and Edwards  2018 ). The risk of ovarian cancer increases with age, particularly in individuals over the age of 50. Those with a history of breast cancer—especially when diagnosed at a younger age—exhibit an elevated risk. Additional risk factors include hormone replacement therapy, tobacco use, asbestos exposure, endometriosis, diabetes, and obesity (Rooth  2013 ; La Vecchia  2017 ). While no foolproof preventive measure exists, factors such as the use of oral contraceptives, childbirth, breastfeeding, and certain surgical procedures—including tubal ligation or hysterectomy—may reduce the risk of ovarian cancer (Figure  1 ) (Lancaster et al.  2015 ). Ovarian cancer is staged from stage I (early) to stage IV (advanced), based on the extent of disease progression. The stages of ovarian cancer are defined as follows (Menon et al.  2018 ): Stage I: The cancer is limited to one or both ovaries. Stage II: The cancer has spread beyond the ovaries but remains limited to the pelvic region. Stage III: The cancer has extended to the abdominal cavity and/or lymph nodes. Stage IV: The cancer has metastasized to distant organs, such as the liver, lungs, or other parts of the body (Figure  2 ). Overview of ovarian cancer: risk factors, prevention, and treatment options. Ovarian cancer is classified into different stages, typically ranging from stage I (early) to stage IV (advanced), based on the extent of the disease. Unraveling the complexities of ovarian cancer depends on understanding its intricate molecular landscape, highlighting the pivotal role of genetic alterations in both tumor initiation and progression—insights that are essential for the development of targeted therapies. Notably, mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 significantly increase the risk of ovarian cancer and are implicated in approximately 5%–15% of cases (Kuchenbaecker et al.  2017 ). Mutations in tumor protein 53 (TP53) contribute to genomic instability and resistance to chemotherapy, particularly in high‐grade serous ovarian cancer (HGSC) (Silwal‐Pandit et al.  2017 ). In contrast, homologous recombination deficiency (HRD), also prevalent in HGSC, associated with increased sensitivity to poly (ADP‐ribose) polymerase (PARP) inhibitors—an important therapeutic approach (Vergote et al.  2022 ). Conversely, low‐grade serous ovarian cancer (LGSC) is characterized by mutations in the mitogen‐activated protein kinase (MAPK) pathway, including KRAS and BRAF, distinguishing it from its high‐grade counterpart (Hendrikse et al.  2023 ). The heterogeneity in estrogen and progesterone expression across ovarian cancer subtypes accentuates the need for tailored hormonal therapies (Modugno et al.  2012 ). Additionally, emerging insights into microsatellite instability (MSI), deficient mismatch repair (dMMR), tumor mutational burden (TMB), and the diverse subtypes highlight the dynamic and evolving landscape of ovarian cancer research (Roudko et al.  2021 ). Importantly, these developments highlight the critical role of molecular analysis in guiding clinical decision‐making and informing personalized treatment strategies. The integration of molecular markers into clinical trials reflects a shift toward precision medicine, offering promising advancements in ovarian cancer research and therapeutic outcomes. Ovarian cancer presents a substantial challenge in the field of oncology, largely due to the development of resistance to conventional chemotherapeutic agents, particularly with cisplatin. Addressing this formidable obstacle requires multifaceted strategies, including the extension of platinum‐free intervals (Sambasivan  2022 ; Gilbert et al.  2023 ), the incorporation of non‐platinum cytotoxic agents (Tomao et al.  2017 ; Dockery et al.  2019 ), and the advancement of molecularly targeted therapies such as PARP inhibitors (Wu, Xu, et al.  2023 ), and immunotherapies (Siminiak et al.  2022 ). Molecular profiling—which includes the evaluation of TMB (Wang et al.  2022 ), and programmed cell death protein 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) expression (Dumitru et al.  2022 )—significantly enhances the precision of both diagnosis and treatment. Recent advancements in drug delivery systems, particularly those employing nanoparticle‐based strategies, have shown considerable promise in improving therapeutic efficacy (Beyene et al.  2021 ; Wu, Yang, et al.  2023 ). However, persistent challenges—such as late‐stage diagnoses, aggressive metastasis, and healthcare disparities—continue to hinder progress in ovarian cancer management. Advancing the field requires a sustained commitment to ongoing research, adequate funding, and cross‐disciplinary collaboration to address the multifaceted nature of the disease. Promising breakthroughs may lie in the strategic integration of existing therapies, the development of more effective treatment protocols, and the cultivation of collaborative frameworks aimed at optimizing patient outcomes. Diagnostic tests for ovarian cancer have traditionally included the CA125 blood test—a widely recognized tumor marker for ovarian cancer and transvaginal ultrasound (Trinidad et al.  2020 ). However, both methods have notable limitations in sensitivity and specificity. Definitive diagnosis often requires surgical intervention to obtain ovarian tissue for histopathological evaluation. In addition, genetic testing can detect mutations linked with an elevated risk of cancer. The classification of ovarian cancer staging follows the International Federation of Gynecology and Obstetrics (FIGO) staging system, which ranges from stage 1 to stage 4, and reflects the extent of disease spread. Treatment requires a multidisciplinary approach, combining surgery—ranging from cytoreductive to fertility‐sparing procedures—with chemotherapy using agents like carboplatin and paclitaxel, tailored to tumor pathology and patient health, and administered postoperatively or as standalone therapy in defined cycles. In advanced cases, personalized treatment strategies may include radiotherapy and targeted agents such as olaparib and bevacizumab (Grunewald and Ledermann  2017 ). Ovarian cancer follow‐up includes clinical assessments and CA125 monitoring. Current treatments face challenges like side effects and chemoresistance (Li et al.  2018 ). Novel, personalized therapies based on genetic and physiological profiles are crucial for improving outcomes, reducing toxicity, and overcoming treatment resistance.

As of March 2024, the International Clinical Trials Registry Platform (ICTRP) lists a total of 923 studies investigated the therapeutic potential of curcumin, covering the period from 1900 to 2024. A significant proportion of these studies employed double‐blind, randomized, and placebo‐controlled trial designs, and consistently reported favorable effects on both clinical outcomes and relevant biomarkers. Notably, metabolic disorders—particularly those associated with obesity and insulin resistance—represent the most extensively studied category, followed by musculoskeletal disorders (Panknin et al.  2023 ). Of the registered clinical studies, 155 have been completed; however, only 40 have yielded public available results. Within this body of research, 118 studies have focused on oncology, with 26 completed and 14 providing accessible outcomes. These cancer‐focused trials have investigated curcumin's therapeutic potential across a range of cancers including, breast cancer (Ryan et al.  2013 ; Miller  2018 ; Ryan Wolf et al.  2018 ; Kalluru et al.  2020 ; Saghatelyan et al.  2020 ), colorectal cancer (Carroll et al.  2011 ; Gunther et al.  2017 ; Cruz‐Correa et al.  2018 ; Howells et al.  2019 ), prostate cancer (Suzuki et al.  2006 ; Hejazi et al.  2013 , 2016 ; Choi et al.  2019 ; Saadipoor et al.  2019 ), pancreatic cancer (Dhillon et al.  2008 ; Parsons et al.  2016 ). Despite encouraging preclinical findings on curcumin's effects in ovarian cancer, clinical evidence supporting its efficacy remains limited. Currently, no pilot studies are underway to evaluate the therapeutic effects of curcumin supplementation specifically in ovarian cancer patients. Nevertheless, ovarian cancer shares significant molecular and pathological associations with other malignancies such as breast, colorectal, endometrial, and liver cancers (Zheng et al.  2018 ). Clinical trials in these related cancers have demonstrated the safety and potential efficacy of curcumin. In breast cancer patients, curcumin has been studied for its impact on a range of clinical outcomes, including radiation‐induced dermatitis, modulation of inflammatory biomarkers, pain management, overall well‐being, and chemotherapy response rates (Ryan et al.  2013 ; Miller  2018 ; Ryan Wolf et al.  2018 ). Similarly, studies in colorectal cancer patients have reported that curcumin is well‐tolerated by healthy tissues (Garcea et al.  2005 ). Moreover, Bayet‐Robert et al. ( 2010 ) investigated the combination of docetaxel and curcumin in 14 patients with metastatic or advanced‐stage breast cancer, indicating the feasibility and potential of such combinatorial approaches in clinical oncology. In this study, six escalating doses of curcumin were evaluated in combination with docetaxel. The maximum tolerated dose was determined to be 6 g/day, while dose‐limiting toxicities (DLTs), primarily grade III diarrhea, emerged at the highest tested dose of 8 g/day. Hematological toxicities were transient and manageable. Notably, significant reductions in carcinoembryonic antigen (CEA) and VEGF levels were observed, indicating potential antiangiogenic activity. Clinically, no cases of disease progression were reported; five patients exhibited partial responses, and three maintained stable disease. These findings highlight the potential efficacy and safety of the curcumin‐docetaxel combination in advanced breast cancer and support its further investigation in a phase II clinical trial. Transitioning curcumin research in ovarian cancer from preclinical to clinical studies presents several major challenges. Curcumin's poor bioavailability mainly restricts its in vivo efficacy. Many preclinical studies rely on high doses or nanoformulations that are not yet standardized for clinical use, complicating translation to human trials. In vitro models often fail to replicate the complexity of the tumor microenvironment, limiting their predictive value. Variations in experimental design, including differences in dosage, treatment duration, and the choice of cell lines or animal models, contribute to inconsistent results. Clinical studies, though few, often suffer from small sample sizes, short durations, and lack of controls. The absence of clearly defined clinical endpoints and validated biomarkers further weakens the strength of these studies. Additionally, potential synergistic effects of curcumin with other therapeutic agents remain unexplored in clinical studies. The biological heterogeneity of ovarian cancer adds another layer of complexity, making uniform treatment responses unlikely. Inconsistent formulation quality and lack of pharmacokinetic monitoring also contribute to mixed results.

Curcumin shows therapeutic promise against chronic diseases like cancer, inflammation, and metabolic disorders. It enhances chemotherapy effectiveness, sensitizes cancer cells, and inhibits tumor growth by targeting multiple molecular pathways, making it a major focus in cancer research. Curcumin's interaction with ovarian cancer progression is polygonal, targeting many cellular pathways involved in malignancy. Firstly, it modulates proliferation pathways such as epidermal growth factor receptor (EGFR) (Choe et al.  2018 ), and activator protein 1 (AP‐1) (Zheng et al.  2022 ), thereby inhibiting uncontrolled cell growth. Secondly, curcumin disrupts cell cycle progression by downregulating cyclin D1 and cyclin E (Weir et al.  2007 ; Montopoli et al.  2009 ), leading to cell cycle arrest and the inhibition of further tumor growth. Additionally, its anti‐inflammatory properties inhibit nuclear factor‐kappa B (NF‐κB) (Fogoros et al.  2006 ), tumor necrosis factor (TNF) and interleukin‐6 (IL‐6) (Sandhiutami, Arozal, Louisa, and Rahmat  2021 ), and cyclooxygenase‐2 (COX‐2) (Afshari et al.  2024 ), suppressing inflammatory responses associated with cancer progression. Curcumin induces apoptosis in ovarian cancer cells by modulating multiple molecular pathways. It downregulates anti‐apoptotic proteins like BCL‐2, Bcl‐XL, and pro‐caspase‐3, while upregulating pro‐apoptotic markers such as p53 and Bcl‐2‐associated X protein (Bax) (Zheng et al.  2004 ; Wahl et al.  2007 ; Seo et al.  2016 ; Shi et al.  2006 ; Watson et al.  2010 ; Ju et al.  2018 ). Curcumin inhibits survival pathways like the phosphatidylinositol 3‐kinase/protein kinase B (PI3K/Akt) pathway (Alharbi et al.  2024 ), thereby impeding cancer cell survival and proliferation. In SKOV3 and A2780 cells, curcumin inhibits the PI3K/AKT pathway by decreasing the p‐AKT/AKT ratio in a dose‐dependent manner, enhancing cytotoxicity (Zheng et al.  2006 ; Yu et al.  2016 ; Dan et al.  2021 ). Interestingly, in SKOV3 cells, BCL‐2 activity decreases, but caspase‐3 levels remain unchanged, suggesting a caspase‐3‐independent apoptotic mechanism (Zhao et al.  2017 ). These findings highlight curcumin's potential to induce apoptosis via cell line‐specific pathways, making it a promising agent for OC treatment. Furthermore, curcumin downregulates anti‐apoptotic proteins like Survivin and BCL‐2, activates p38 MAPK, and triggers apoptosis independently of p53 in SKOV3 cells (Watson et al.  2010 ; Qian et al.  2011 ; Chen et al.  2013 ). In CaOV3 cells, curcumin activates AMPK and induces p53 phosphorylation via p38; this effect decreases with AMPK/p38 inhibition (Pan et al.  2008 ). When combined with TRAIL, curcumin enhances apoptosis by activating mitochondrial and death receptor pathways (Wahl et al.  2007 ). Curcumin derivatives like ST03, ST08, and B19 further induce cytotoxicity by activating caspase‐9 and caspase‐3, highlighting their potential as effective agents against OC (Zhang et al.  2012 ; Qu et al.  2013 ; Koroth et al.  2019 ). Furthermore, curcumin suppresses angiogenesis by downregulating vascular endothelial growth factor (VEGF) (Lin et al.  2007 ), thereby limiting the formation of new blood vessels crucial for tumor growth and metastasis. It also interferes with invasion and metastasis by downregulating matrix metalloproteinase‐9 (MMP‐9) (Pei et al.  2016 ), and adhesion molecules like integrins, hindering cancer cell migration and invasion into surrounding tissues. Curcumin also interacts with non‐coding RNAs, particularly circular RNAs (circRNAs), which are increasingly recognized as therapeutic targets in ovarian cancer (Ravindran et al.  2023 ). Emerging evidence highlights its potential to regulate circular RNA networks, notably the circular RNA derived from pleckstrin homology domain‐containing family M member 3/microRNA‐320a/suppressor of morphogenesis in genitalia‐1 (circ‐PLEKHM3/miR‐320a/SMG1) axis, suppressing cell proliferation, inducing apoptosis, and reducing tumorigenesis (Sun and Fang  2021 ). Curcumin regulates microRNAs (miRNAs), such as miR‐214 (Zhang et al.  2017 ), miR‐124 (Zhao et al.  2017 ), and miR‐9 (Liu et al.  2023 ), affecting cisplatin‐resistance and cell growth. It also upregulates the expression of the tumor‐suppressive long non‐coding RNA (lncRNA), maternally expressed 3 gene (MEG3) (Zhang et al.  2017 ). Its epigenetic influence, potential in innovative combination therapies, and the challenges associated with its application underscore the need for continued research to unlock the potential of curcumin in revolutionizing ovarian cancer treatment. Schematic overview of curcumin's anticancer mechanism in ovarian cancer pathways is presented in Figure  3 . Schematic overview of curcumin's anticancer mechanism in ovarian cancer pathways. Curcumin's diverse anticancer effects in ovarian cancer involve modulation of oncogenes (red boxes: AKT (protein kinase B), RAS (rat sarcoma), NOX4 (NADPH oxidase 4), NF‐κB (nuclear factor‐kappa B), MET (mesenchymal–epithelial transition), HIF1‐α (hypoxia‐inducible factor 1‐alpha), PI3K (phosphoinositide 3‐kinase), MDM2 (mouse double minute 2 homolog), STAT3 (signal transducer and activator of transcription 3), TNF‐α (tumor necrosis factor‐alpha)), tumor suppressors (light blue boxes: p53 (tumor protein 53), PTEN (phosphatase and tensin homolog), LKB1 (liver kinase B1), ATM/ATR (ataxia telangiectasia mutated/ATM and Rad3‐related), BRCA1 (breast cancer 1)), miRNA regulation (violet boxes: miR‐135a, miR‐143, miR‐199a, miR‐20a, miR‐203, miR‐21, miR‐25, miR‐433, miR‐551b), cell cycle regulation (green boxes: CDK6 (cyclin‐dependent kinase 6), β‐catenin (beta‐catenin), GSK‐3β (glycogen synthase kinase 3 beta), FOXO3 (forkhead box O3), Cyc‐D3 (cyclin D3)), apoptosis modulation (light brown boxes: PARP (poly ADP‐ribose polymerase), BCL2 (B‐cell lymphoma 2), BAX (BCL2‐associated X protein), APAF‐1 (apoptotic peptidase activating factor 1)), metabolism/energy sensing mechanisms (blue boxes: AMPK (AMP‐activated protein kinase), TSC (tuberous sclerosis complex), mTOR (mechanistic target of rapamycin), ULK1 complex (Unc‐51 like autophagy activating kinase 1 complex), class III PI3K complex), and other genes relevant to ovarian cancer (light green boxes: TGF‐β (transforming growth factor‐beta), HOXA10 (homeobox A10), CSN2 (casein kinase II subunit alpha), and Smad (mothers against decapentaplegic homolog)).

The authors have nothing to report.

Ovarian cancer, the second most prevalent gynecological malignancy worldwide, presents a significant global health challenge. In 2020, an estimated 313,959 new cases were diagnosed, resulting in 207,252 deaths worldwide (Sung et al.  2021 ). Although relatively rare compared to other cancers, ovarian cancer ranks eighth in global incidence. Notably, approximately 75% of cases are diagnosed at advanced stages, with survival rates falling below 50% (Torre et al.  2018 ). In South Korea, ovarian cancer accounts for 2.5% of all female cancer cases, with survival rates ranging from 95% in early‐stage diagnoses to approximately 15% in advanced stages (Korea Central Cancer Registry  2022 ). In the United States, an estimated 19,710 new cases and 13,270 deaths were projected for 2023, with a 5‐year relative survival rate of 50.8%. This overall figure masks significant variation by stage, with survival rates ranging from 92.4% for localized disease to 31.5% for distant metastasis (Siegel et al.  2023 ). Ovarian cancer is classified into three main histologic types, with epithelial ovarian cancer accounting for approximately 90% of cases, while germ and stromal cell types are less common. General symptoms of ovarian cancer often include persistent and unexplained abdominal or pelvic pain, which may vary from a dull, aching discomfort to sharp, intense pain (La Vecchia 2017 ; Chandra et al.  2019 ; Boussios et al.  2019 ). The precise causes of ovarian cancer remain elusive, but several identifiable risk factors have been recognized. Ovarian cancer risk rises with age, predominantly affecting postmenopausal women. Inherited genetic mutations like BRCA1 and BRCA2 significantly heighten the likelihood of developing ovarian cancer, and a family history of ovarian or breast cancer can also elevate one's risk (Lancaster et al.  2015 ). The asymptomatic progression of ovarian cancer has earned it the moniker “silent killer”, reflecting the persistent challenges associated with early detection. The 5‐year survival rate drops significantly when the disease is diagnosed at an advanced stage. The clinical complexity of advanced‐stage ovarian cancer—characterized by limited treatment options and heterogeneous histological subtypes—continues to present significant obstacles to effective therapeutic intervention (Jacobs et al.  2016 ). The standard treatment for ovarian cancer primarily involves platinum‐based chemotherapy, often in combination with paclitaxel or the antiangiogenic agent bevacizumab. Despite its initial effectiveness, the development of resistance—particularly to bevacizumab—remains a major challenge, leading to disease recurrence or progression in 70%–80% of patients following primary treatment (Mai et al.  2022 ). Furthermore, anticancer drugs are associated with adverse effects, including lymphopenia, tiredness, diarrhea, fatigue, and loss of appetite. In response, increased awareness of symptoms and proactive management of risk factors, including age, genetic mutations, and hormonal therapy, are of significant importance. Personalized prognostic discussions are essential, and should consider factors such as the specific type of ovarian cancer and the patient's overall health status. Current research continues to focus on developing effective early detection methods and innovative treatment strategies to address the considerable global health challenge posed by ovarian cancer. Amid ongoing challenges in disease management, plant‐derived bioactive compounds have emerged as promising alternatives for combating a range of conditions (Guo et al.  2018 ; Eze et al.  2022 ; Uma Reddy et al.  2022 ), including cancer (Redkar and Jolly  2003 ; Ma et al.  2021 ). Curcumin—a bioactive compound derived from rhizomes of turmeric ( Curcuma longa ), extensively investigated for its pharmaceutical properties in both in vitro and in vivo studies and clinical studies (Karthikeyan et al.  2021 ; Gao et al.  2022 ; Smirnova et al.  2023 ; Sureshbabu et al.  2023 ; Tuong et al.  2023 ; Lan et al.  2024 ). Many studies have demonstrated the biological effects of curcumin on multiple cellular functions, many of which are crucial to its anticancer activity (Patel et al.  2020 ; Pourbagher‐Shahri et al.  2021 ; Mohammadi et al.  2022 ). Curcumin has demonstrated efficacy in modulating signaling pathways involved in cellular proliferation, apoptosis, and angiogenesis in various malignancies (Tomeh et al.  2019 ; Zoi et al.  2022 ; Singh et al.  2023 ). Notably, clinical studies involving human participants have shown that curcumin is well‐tolerated, safe, and non‐carcinogenic (Gupta et al.  2013 ; Soleimani et al.  2018 ). In the context of ovarian cancer, curcumin functions as an anticancer agent by suppressing tumorigenesis, enhancing the efficacy of radiotherapy and chemotherapy, and minimizing damage to normal cells (Pourhanifeh et al.  2020 ). Curcumin's anticancer effects against ovarian cancer have been demonstrated in both in vitro and in vivo studies. Furthermore, nanoformulations of curcumin markedly enhance its bioavailability and therapeutic efficacy. However, clinical evidence in humans remains limited. Critical questions concerning the optimal dosage, long‐term safety, and pharmacokinetics of curcumin in ovarian cancer patients have yet to be fully resolved. In this review, we first provide a brief overview of ovarian cancer, followed by an examination of curcumin's emerging role in its treatment. We also shed light on the existing research gaps and outline a roadmap for future studies aimed at fully harnessing curcumin's therapeutic potential in the management of ovarian cancer.

The authors declare no conflicts of interest.