{"paper_id":"2706cda1-f421-40b4-9dcb-03e1360def76","body_text":"Cancer remains one of the leading causes of mortality and morbidity\nworldwide; as per recent statistics, approximately two million new cases and\nmore than 600,000 deaths are projected to occur in the United States in 2022\n[ 1 ]. Ovarian cancer is considered the third\nmost common gynecological tumor\nafter cervical and uterine cancers; however, the remarkable aggressivity has\nmade it the leading cause of cancer deaths in women as well as the fourth rank\nof death among all fatal diseases in women [ 2 ][ 3 ][ 4 ].\nStatistical studies state\nthat annually over 240,000 new cases are diagnosed with ovarian cancer, and\napproximately 380,000 deaths occur per year worldwide [ 5 ][ 6 ].\nWorld health organization has histologically classified ovarian tumors\nbased on histogenetic principles according to the tumor derivation from\ncoelomic surface epithelial cells, mesenchyme, and germ cells [ 7 ]. The majority\nof malignant ovarian tumors are considered to be epithelial ovarian cancers,\nwhich are further divided into mucinous, serous, clear cell, mixed epithelial\ntumors, transitional cell tumors (known as Brenner tumors), carcinosarcoma,\nendometrioid, undifferentiated carcinoma, and other histological types [ 8 ].\nMoreover, some types, such as clear cell and endometrioid carcinomas, have been\nassociated with endometriosis, another gynecological disorder [ 8 ][ 9 ].\nImportantly, this most common type of ovarian cancer, epithelial ovarian\ncancer, has a 5-year survival rate of 45.6% and could be caused by hormone\nimbalance during physiological processes such as ovulation and pregnancy, as\nwell as exogenous estrogen and progesterone [ \n10 ][ 11 ][ 12 ].\nThe primary and standard for ovarian cancer treatment broadly includes\ndebulking surgery to no residual disease followed by platinum-based\nchemotherapy, accompanied by anti-angiogenic agents in a patient who has\nsuboptimal debulked and advanced (stage III-IV) ovarian cancer; however, the\noutcomes\nof the disease management are complicated because of different factors [ 13 ].\nFirstly, ovarian cancer is considered a heterogeneous group of malignancies\nrepresenting different etiology and molecular biology, even in a similar\nhistological class [ 14 ]. Secondly, it is\ndocumented that the early symptoms of\nthis type of cancer are occult. Moreover, the identification of the tissue\ntypes and whether the tumor is benign or malignant is quite challenging [ 15 ].\nNotably, the 5-year survival rate for ovarian cancers is reported to be 93%\nwhen diagnosed at an early stage but declines to just over 13% when diagnosed\nat an advanced stage [ 5 ]. The occultness of\nearly symptoms, the poor prognosis\nof the disease in advanced stages, and the fact that about 70% of ovarian\ncancer diagnoses are made in advanced stages [ \n15 ] ultimately lead to\nnon-responsiveness to therapeutic strategies and reduced rates of survival to\nthe point where 63% of cases ends in death [ \n15 ]. In addition to all this, the\nadverse effects of common treatment methods, such as the invasiveness of\nsurgery and the toxicity of chemotherapy on non-target tissues, which cause\ninfertility [ 16 ][ 17 ], anemia [ 18 ][ 19 ], infection [ 20 ][ 21 ], bleeding [ 22 ],\ninsomnia and depression [ 23 ][ 24 ][ 25 ],\ndiarrhea, and constipation [ 26 ][ 27 ] have led\nresearchers to desire to find an alternative to the standard treatments\nstrongly.\nThe design and development of novel pharmaceuticals with fewer adverse\neffects and improved antitumoral activity are considered one of the main\nstrategies to confront the previous insufficiencies of ovarian cancer\ntherapeutic approaches [ 28 ][ 29 ]. Nevertheless, this solution itself faces\ndefects such as being costly, time-consuming approval processes, and a lack of\nability to eliminate all the previous adverse effects. Poly (ADP-ribose)\npolymerase (PARP) inhibitors, for example, benefits from homologous recombination\ndeficiency, particularly in the carriers of breast cancer gene 1 and 2\n(BRCA1/2) mutation [ 30 ][ 31 ]. Furthermore, aurora kinase inhibitors in certain\ntumor types, such as epithelial ovarian cancer, have been suggested by\nextensive recent preclinical studies [ \n32 ][ 33 ]. In addition, the\ndetermined\nmutations (e.g.,  ARID1A  mutations) along with aberrant signaling\npathways (e.g., phosphatidylinositol 3-kinase [PI3K]/Akt/mTOR pathway) are\nconsidered the main characteristics of ovarian clear cell carcinoma and\nendometrioid ovarian carcinoma proposing further therapeutic targets [ 34 ][ 35 ][ 36 ][ 37 ].\nFortunately, herbal compounds and traditional Chinese medicine have been\ndemonstrated in several studies to provide desired features such as antitumor\n[ 38 ], anti-inflammatory [ 39 ], antimicrobial [ 39 ], antioxidant [ 40 ],\nmetabolism\nregulation [ 41 ], antidiabetic [ 42 ], antineurodegeneration [ 43 ],\ncardioprotective [ 44 ], enhancing the effects\nof chemotherapy [ 45 ], and reducing\nthe destructive adverse effects of pharmaceuticals in non-target healthy\ntissues [ 46 ]. The present study aimed to\nassess the antitumoral activity of\nherbal products against ovarian cancer, introduce Icariin, a novel dietary\nphytochemical with extensive beneficial properties, and finally review its\ntherapeutic performance against ovarian cancer.\n\nIt is well known that cancer does not arise due to a single target\ndisruption; however, it involves consecutive genetic and epigenetic changes,\nall of which lead to a myriad of altered signaling pathways. Hence, full\nknowledge of the complicated character of cancer still confronts a\nhard-to-estimate number of challenges [ 47 ].\nIn addition, the involvement of\nmultiple signaling pathways via sequential genetic and epigenetic changes\nconfirms that the proposed therapeutic approach must be capable of modulating\nthe altered factors in addition to representing safety and reasonable adverse\neffects, not to decrease the quality of life of survivors [ 29 ][ 47 ][ 48 ][ 49 ].\nInterestingly,\nphytochemicals, which are abundantly found in the daily diet and are\ninexpensively available to the public, propose the potential for such a\nfunction widely [ 50 ][ 51 ][ 52 ][ 53 ][ 54 ][ 55 ][ 56 ].\nIt is extensively reported that natural compounds are capable of\naltering key regulators of tumor glycolysis signaling pathways, including\nglucose transporters, phosphofructokinase, hexokinases, lactate dehydrogenase,\nand pyruvate kinase and thereby affecting tumor cells' energy sources to\nrestrict their proliferation. Additionally, the synthesis, activation,\nstabilization, and accumulation of hypoxia-inducible factor 1-a in cancerous cells\nare affected by\nphytochemicals via modulation of PI3K/Akt/mTOR and MAPK/ERK signaling pathways\n[ 47 ]. It is documented that phytochemicals\ncan modulate apoptotic and\nautophagic signaling pathways in cancer, making these compounds promising\ntherapeutic options [ 57 ]. Indeed, numerous\nstudies demonstrated that\nphytochemicals affect cell survival signaling pathways in a pleiotropic and\npoorly specific approach; however, the modulation of reactive oxygen species\n(ROS) levels leads to activation of survival or a pro-apoptotic and\npro-autophagic mechanism in the targeted tumor cell is common among all of them\n[ 58 ]. The regulatory role of the natural\ncompounds on the crosstalk between\napoptosis and autophagic flux could determine the destination of cancerous\ncells [ 59 ].\nIn addition to this antioxidative property of phytochemicals, these\nbioactive compounds are capable of targeting the signaling pathway related to\ntoll-like receptor4 (TLR4), a well-known pattern recognition receptor that\nplays a remarkable role in the host immune system in which its triggering is\nfollowed by the secretion of pro-inflammatory cytokines and chemokines and the\nactivation of both innate and adaptive immunity, leading to anti-inflammatory\nresponses and cancer prevention [ 60 ]. More\nimportantly, the combined\nadministration of phytochemicals with chemotherapeutics, known as\npolychemotherapy, could enhance anticancer activity by inhibiting\nchemoresistance via downregulation of oncogene pathways, including transforming\ngrowth factor -β (TGF- β), matrix metalloproteinase (MMP)-2, PI3K/Akt, EMT,\nNF-κB, and AP-1, augmentation of apoptosis induction in cancer cells, and\nsuppression of cancer metastasis and proliferation [ \n61 ]. In addition, the\neffects of selected phytochemicals or their combination on Nrf2 and NF-κB\nactivities represent cancer prevention and therapy properties [ 62 ].\nFurthermore, the Janus kinase (JAK)/signal transducer and activator of\ntranscription (STAT) signaling pathway, which its aberrant activation leads to\ntumorigenesis, is suppressed by phytochemicals leading to impeding cancer cell\ngrowth [ 63 ].\n\nSimilar to the mentioned content in the previous section about\nphytochemicals' potential therapeutic role through modulation of several\nsignaling pathways in all types of cancers, many studies have stated these\nbeneficial effects in ovarian cancer. Resveratrol, for instance, is recognized as\na preventive and therapeutic agent for ovarian cancer since it is capable of\ntargeting a variety of oncogenic and oncosuppressive pathways, including\ncancerous cell proliferation, metastasis, autophagy, apoptosis, and\nsensitization [ 64 ]. Furthermore, quercetin, a\nwell-known phytoestrogen, is\nreported to be able to attenuate metastatic features of human ovarian cancer\ncells by inactivation of PI3k/Akt, Ras/Raf pathways, and epidermal growth\nfactor receptor expression, which are involved in ovarian tumor cell survival\nand proliferation along with modulating the levels of migration and adhesion\nsignaling molecules such as occludin, claudin-4, and claudin-11 [ 65 ].\nSimilarly, the decrement in antiapoptotic molecules (e.g., Bcl-2 and Bcl-xL)\nbut the increment in pro-apoptotic molecules (e.g., Bad, Bax, Bid, caspase-3,\nand caspase-9) revealed that quercetin could inhibit the growth and survival of\nmetastatic ovarian cancer cells [ 66 ]. Also,\nsuch a function has been reported\nfollowing the interplay of quercetin and microRNAs [ \n67 ]. The regulation of\novarian cancer cells carcinogenesis through modulation of the Wnt/β-catenin\nsignaling pathway [ 68 ], suppression of\novarian cancer cells metastasis via\naffecting the JAK/STAT3 pathway [ 69 ], and\ndisrupting tumor proliferation,\ngrowth, and angiogenesis via downregulation of PI3K/Akt and MEK/ERK1/2 axes are\ndesired properties of curcumin [ 70 ].\nFortunately, the findings are not limited\nto the mentioned examples, and many further studies have provided similar\nreports regarding other phytochemicals [ \n71 ][ 72 ][ 73 ].\n\nThe dried leaf of  Epimedium , an herbaceous plant belonging\nto the family of  Berberidaceae , is known as Epimedii herba. This\nplant\nis abundantly found in different parts of Asia as well as Europe [ 74 ].  E.\nherba\n  has been prescribed for over 2000 years in Eastern Asia countries by\ntraditional Chinese medicine practitioners for its therapeutic functions [ 75 ].\nChronic disorders such as female sterility, chronic bronchitis, general edema,\nleucopenia, kidney disorders, viral myocarditis, and hypertension are among the\nmost important conditions that  E. herba  can provide a beneficial\nalleviating role [ 74 ][ 75 ]. The therapeutic properties of  E. herba  are\nattributed to bioactive compounds, including flavonoids, terpenoids, and other\nchemicals such as steroids, acids, lignans, alkaloids, and anthraquinones [ 76 ].\nIt has been determined that there are 53 different flavonoids in this plant,\nincluding baohuoside I [ 76 ], ginkgetin [ 77 ], quercetin [ 78 ], robinetin [ 75 ],\napigenin [ 75 ], luteolin [ 79 ], hyperin [ \n77 ], and icariin [ 80 ].\nIcariin, 2- (4′- methoxylphenyl)- 3- rhamnosido- 5- hydroxyl- 7-\nglucosido- 8- (3′- methyl- 2-butylenyl)-4- chromanone, is a well-known\npentenylated flavonoid glycoside monomer derived from  E. herba\n  [ 80 ].\nThis phytoestrogen was first isolated and identified in 1990 and is believed to\nexert several favored biological characteristics, including antiosteoporosis,\nantidepression, anti-inflammatory, antioxidant, and antitumor activities [ 81 ][ 82 ].\nThe modulation of various signaling pathways such as MiR-223-3p/ NALP3,\nIGF-1, TLR4/ NF-κB, PI3K/Akt, NFκB/ NALP3, Wnt1/ β-catenin, and Nrf-2 are\ndocumented as the basic mechanisms by which icariin possess its pharmacological\nand therapeutical functions [ 77 ].\nThe inhibition of interleukin-1β (IL-1 β)/ TGF-β-mediated\nactivation of renal fibroblasts is the mechanism involved in the attenuation of\nrenal fibrosis in chronic renal disease by icariin [ \n83 ]. Furthermore, icariin\ncan suppress cystitis induced by cyclophosphamide chemotherapy by the\nupregulation of the Nrf-2/HO-1 signaling pathway as well as the downregulation\nof the NF-кB pathway [ 84 ]. The\nneuroprotective characteristics of this\nphytochemical against Alzheimer's and Parkinson's diseases are mediated by\naffecting several biomolecules and molecular pathways such as amyloid precursor\nprotein, β-site amyloid precursor\nprotein cleaving enzyme 1 (BACE1), insulin-degrading enzyme, ERK1/2, GSK-3,\nNF-κB, Nrf2, and PI3K [ 80 ]. The inhibition of\nmyocardial apoptosis, the\nprevention of inflammation on endothelial cells, the improvement of the immune\nsystem function, and the activation of HO1/Nrf2 signaling pathways are reported\nas the modulatory mechanisms by which icariin exerts its therapeutical\nproperties against cardiovascular disorders [ \n85 ][ 86 ]. Furthermore, the\nantimicrobial function of this phytoestrogen, such as ameliorating Escherichia\ncoli lipopolysaccharide-mediated endometritis, is suggested to be performed by\ninhibiting oxidative stress and inflammation [ \n87 ]. In addition, the desired\neffects of icariin on the skeletal system, such as the alleviation of\nosteoarthritis and inhibition of RANKL-induced osteoclast genesis, are mediated\nby the regulatory role on the autophagy of chondrocytes, modification of\nPI3K/AKT/mTOR signaling, inhibition of reactive oxygen species (ROS) levels,\nand reduction in the expression of  NOX1  and  NOX4  [ 88 ][ 89 ].\nMoreover, the immunoregulatory and anti-inflammatory properties of icariin have\nintroduced this phytochemical as a novel promising medicament to confront\ndisorders related to the immune system, including inflammatory bowel diseases,\nasthma, multiple sclerosis, rheumatoid arthritis, lupus nephritis,\natherosclerosis, and cancer via the restoration of aberrant signaling pathways,\nmodulation of the functions and activation of immune cells, and regulation of\nthe release of inflammatory factors [ 90 ].\nMany studies have demonstrated the therapeutic function of icariin\non several types of cancers, each of which was achieved by affecting a variety\nof cellular regulatory mechanisms. The amelioration of benign prostatic\nhyperplasia is demonstrated, which was achieved through the activation of the\nAMPK pathway as well as its antiproliferative (revealed histological\nmanifestations), pro-apoptotic (upregulated  Bax  and\ndownregulated  Bcl-2 ),\nantioxidative (reduced malondialdehyde, catalase exhaustion, and decreased\nglutathione depletion), and anti-inflammatory (reduced IL-6 and tumor necrosis\nfactor [TNF]-α levels) properties [ 91 ].\nMoreover, icariin-induced upregulation\nof miR-7 expression and subsequent inhibition of PI3K/AKT and Raf1/ERK1/2\nsignaling pathways leads to suppression of benign prostatic hyperplasia cells\nproliferation, migration, and promotion of apoptosis [ 92 ]. The inhibition of\nSIRT6/NF-κB by icariin cause redox-mediated apoptosis in triple-negative breast\ncancer cells [ 93 ]. Furthermore, the\nsuppression of autophagy and the regulation\nof the MELK-mediated PI3K/Akt signaling pathway are recognized as another\nmechanism by which icariin induces apoptosis in MCF-7 breast cancer cells [ 94 ][ 95 ].\nModification of the mTOR/PI3K/Akt signaling pathway by icariin leads to\nboth apoptosis and autophagy and, finally, inhibition of the growth of human\ncervical cancer cells [ 96 ]. The reduction of\nTLR4/MyD88/NF-κB and Wnt/β-catenin\npathways upon icariin administration leads to the alleviation of cervical\ncancer [ 97 ]. In lung cancer, it is\ndemonstrated that icariin is able to target\nthe miR‑205‑5p/PTEN axis leading to the modulation of the PI3K/Akt signaling\npathway and inhibition of tumor progression [ \n98 ]. The activation of the\nmitochondrial apoptotic pathway is reported as another mechanism that enables\nicariin to treat lung cancer [ 99 ]. In\naddition, the therapeutic effects of\nicariin on other types of cancer such as gastric, pancreatic, colon, and human\noral squamous cell carcinoma are reported [ \n100 ][ 101 ][ 102 ][ 103 ].\n\nSimilar to the other types of cancer mentioned earlier, icariin\ncan prevent the proliferation and progression of ovarian cancer. Indeed, a\nmulti-dimensional spectrum-effect relationship study, a scientific method based\non the fingerprint of traditional Chinese medicines, determines the correlations\nbetween fingerprint and activity and proposes the antitumor activity of icariin\nagainst ovarian cancer [ 104 ]. Furthermore, a\nstudy based on network\npharmacology suggested that icariin can target a variety of signaling\nbiomolecules such as MMP-9, PIK3CA, STAT3, TNF, ERBB2, PIK3CA, mTOR, KDR, IL-2,\nand F2 in ovarian cancer SKOV3 cell line all of which leading to the induction\nof apoptosis and inhibition of proliferation through the suppression of\nPI3K/Akt signaling pathway [ 105 ]. Similarly,\na most recent network\npharmacology-directed experimental investigation demonstrated that in SKOV3\ncells, icariin could induce apoptosis via affecting pro-apoptotic markers,\nincluding Bcl-xL, Bax, and caspase-3 as well as disrupting the activation of\nthe NF-κB pathway and modulation of PI3K/Akt pathway [ 106 ].\nIn vitro studies have revealed that the functions of icariin on\novarian cancer cell lines are achieved through the modulation of autophagy and\nthe promotion of apoptosis mediated by several signaling pathways [ 107 ]. In\novarian cancer A2780 cells, icariin downregulated the miR-21 expression,\nupregulated PTEN and RECK protein expression, and reduced pro-apoptotic Bcl-2\nprotein levels suggesting the regulatory role of icariin on ovarian cancer\ncells proliferation, apoptosis by modification of miR-21 expression, and the\nmentioned downstream proteins [ 107 ].\nFurthermore, increased levels of\napoptosis, higher levels of ROS, and altered cell cycle have resulted after the\nadministration of icariin on OVCAR-3 ovarian cancer cells suggesting the\ncytotoxicity and apoptosis of this phytochemical against ovarian cancer cells\n[ 108 ]. Similar results regarding the\ncytotoxicity of icariin against ovarian\ncancer cells have been reported in SKOV-3 cells [ \n109 ]. Furthermore, a recent\nstudy stated that the inhibition of proliferation, the stalled cell cycle, and\nthe promotion of apoptosis via disruption of the TNKS2/Wnt/ β-catenin pathway\nmediated by the upregulation of  miR-1-3p  could be achieved after\ntreatment of ovarian SKOV-3 cells with icariin [ \n110 ].\nIn addition to the typical ovarian tumors, icariin can be\nconsidered a good choice for phenotypes that are more difficult to respond to\nand/or do not respond to the current chemotherapeutic strategies in the clinic.\nIn the multidrug-resistant phenotype of SKVCR cells, for example, Jiang  et\nal . revealed that icariin could activate the mTOR signaling pathway,\nfollowed by autophagy inhibition, apoptosis promotion, and suppression of\novarian cancer cell proliferation and tumorigenesis [ 111 ]. Also, these findings\nsuggest that the antitumor activity of icariin represents a solution for\nmultidrug-resistance types of ovarian cancer [ \n111 ]. In addition, icariin could\nenhance the chemosensitivity of a common chemotherapeutic (cisplatin)-resistant\nphenotype of SKVCR cells via the inhibition of autophagy, induction of\napoptosis, promoting G1/S cell cycle transition, and activation of the\nAkt/mTOR/ATG5 pathway [ 112 ].\n\nThe current study revealed that reviewed investigations suggest\npromising therapeutical properties of icariin against ovarian cancer, which\nresulted from the regulatory role of this phytochemical on different signaling\npathways determining the proliferation and growth or apoptosis and death of\ntumoral cells. Nevertheless, the current knowledge is limited to cellular\nstudies. Hence, further experimental and clinical investigations are crucially\nrequired to assess the final safety and efficacy of icariin.\n\nThe authors declared that have no conflict of interest.","source_license":"CC-BY-4.0","license_restricted":false}