Anti-Cancer Agents in Medicinal ChemistryAnti-Cancer Agents in Medicinal ChemistryAnti-Cancer Agents in Medicinal Chemistry1871-52061875-5992Bentham Science64428910.2174/0118715206282904240122063914OncologyResearch ArticleDrug Repositioning for Ovarian Cancer Treatment: An UpdateCavalluzziMariainfo@benthamscience.netVialeMaurizioinfo@benthamscience.netRotondoNatalieinfo@benthamscience.netFerraroValeriainfo@benthamscience.netLentiniGiovanniinfo@benthamscience.netDepartment of Pharmacy — Drug Sciences, University of Bari Aldo MoroUOC Biotherapy, IRCCS San Martino HospitalPharmacy - Drug Sciences, University of Bari Aldo Moro1504202424863764707012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1871-5206/article/view/644289

Ovarian cancer (OC) is one of the most prevalent malignancies in female reproductive organs, and its 5-year survival is below 45%. Despite the advances in surgical and chemotherapeutic options, OC treatment is still a challenge, and new anticancer agents are urgently needed. Drug repositioning has gained significant attention in drug discovery, representing a smart way to identify new clinical applications for drugs whose human safety and pharmacokinetics have already been established, with great time and cost savings in pharmaceutical development endeavors. This review offers an update on the most promising drugs repurposable for OC treatment and/or prevention.

Drug repositioningovarian cancermetforminstatinsbisphosphonateslubeluzole.Stewart, C.; Ralyea, C.; Lockwood, S. Ovarian cancer: An integrated review. Semin. Oncol. Nurs., 2019, 35(2), 151-156. doi: 10.1016/j.soncn.2019.02.001 PMID: 30867104Cheng, Y.H.; Wang, C.H.; Hsu, K.F.; Lee, G.B. Integrated microfluidic system for cell-free DNA extraction from plasma for mutant gene detection and quantification. Anal. Chem., 2022, 94(10), 4311-4318. doi: 10.1021/acs.analchem.1c04988 PMID: 35235296Webb, P.M.; Jordan, S.J. Epidemiology of epithelial ovarian cancer. Best Pract. Res. Clin. Obstet. Gynaecol., 2017, 41, 3-14. doi: 10.1016/j.bpobgyn.2016.08.006 PMID: 27743768Devouassoux-Shisheboran, M.; Genestie, C.; Ray-Coquard, I. Dualistic classification of epithelial ovarian cancer: Is it clinically relevant? Bull. Cancer, 2016, 103(3), 252-258. doi: 10.1016/j.bulcan.2015.12.005 PMID: 26853278McCluggage, W.G.; Singh, N.; Gilks, C.B. Key changes to the World Health Organization (WHO) classification of female genital tumours introduced in the 5th edition (2020). Histopathology, 2022, 80, 762-778.Liu, H.; Xu, Y.; Ji, J.; Dong, R.; Qiu, H.; Dai, X. Prognosis of ovarian clear cell cancer compared with other epithelial cancer types: A population-based analysis. Oncol. Lett., 2020, 19(3), 1947-1957. doi: 10.3892/ol.2020.11252 PMID: 32194689Lee, J.M.; Minasian, L.; Kohn, E.C. New strategies in ovarian cancer treatment. Cancer, 2019, 125(S24), 4623-4629. doi: 10.1002/cncr.32544 PMID: 31967682Gonzalez-Fierro, A.; Dueñas-González, A. Drug repurposing for cancer therapy, easier said than done. Semin. Cancer Biol., 2021, 68, 123-131. doi: 10.1016/j.semcancer.2019.12.012 PMID: 31877340Chong, C.R.; Sullivan, D.J., Jr New uses for old drugs. Nature, 2007, 448(7154), 645-646. doi: 10.1038/448645a PMID: 17687303Parvathaneni, V.; Kulkarni, N.S.; Muth, A.; Gupta, V. Drug repurposing: A promising tool to accelerate the drug discovery process. Drug Discov. Today, 2019, 24(10), 2076-2085. doi: 10.1016/j.drudis.2019.06.014 PMID: 31238113Nunes, M.; Henriques, A.M.; Bartosch, C.; Ricardo, S. Recycling the purpose of old drugs to treat ovarian cancer. Int. J. Mol. Sci., 2020, 21(20), 7768. doi: 10.3390/ijms21207768 PMID: 33092251Kobayashi, Y.; Banno, K.; Kunitomi, H.; Tominaga, E.; Aoki, D. Current state and outlook for drug repositioning anticipated in the field of ovarian cancer. J. Gynecol. Oncol., 2019, 30(1), e10. doi: 10.3802/jgo.2019.30.e10 PMID: 30479094Warburg, O. The metabolism of carcinoma cells. J. Cancer Res., 1925, 9(1), 148-163. doi: 10.1158/jcr.1925.148Li, W.; Zhang, X.; Sang, H.; Zhou, Y.; Shang, C.; Wang, Y.; Zhu, H. Effects of hyperglycemia on the progression of tumor diseases. J. Exp. Clin. Cancer Res., 2019, 38(1), 327. doi: 10.1186/s13046-019-1309-6 PMID: 31337431Shahid, R.K.; Ahmed, S.; Le, D.; Yadav, S. Diabetes and cancer: Risk, challenges, management and outcomes. Cancers, 2021, 13(22), 5735. doi: 10.3390/cancers13225735 PMID: 34830886Karimi, F.; Dinarvand, N.; Sabaghan, M.; Azadbakht, O.; Ataee, S.; Kharazinejad, E.; Moazamfard, M. Diabetes and ovarian cancer: Risk factors, molecular mechanisms and impact on prognosis. Endocrine, 2023. doi: 10.1007/s12020-023-03477-6 PMID: 37552417Nasri, H.; Rafieian-Kopaei, M. Metformin: Current knowledge. J. Res. Med. Sci., 2014, 19(7), 658-664. PMID: 25364368Evans, J.M.M.; Donnelly, L.A.; Emslie-Smith, A.M.; Alessi, D.R.; Morris, A.D. Metformin and reduced risk of cancer in diabetic patients. BMJ, 2005, 330(7503), 1304-1305. doi: 10.1136/bmj.38415.708634.F7 PMID: 15849206Wheaton, W.W.; Weinberg, S.E.; Hamanaka, R.B.; Soberanes, S.; Sullivan, L.B.; Anso, E.; Glasauer, A.; Dufour, E.; Mutlu, G.M.; Budigner, G.R.S.; Chandel, N.S. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife, 2014, 3, e02242. doi: 10.7554/eLife.02242 PMID: 24843020Adekola, K.; Rosen, S.T.; Shanmugam, M. Glucose transporters in cancer metabolism. Curr. Opin. Oncol., 2012, 24(6), 650-654. doi: 10.1097/CCO.0b013e328356da72 PMID: 22913968Li, L.; Wang, L.; Li, J.; Fan, Z.; Yang, L.; Zhang, Z.; Zhang, C.; Yue, D.; Qin, G.; Zhang, T.; Li, F.; Chen, X.; Ping, Y.; Wang, D.; Gao, Q.; He, Q.; Huang, L.; Li, H.; Huang, J.; Zhao, X.; Xue, W.; Sun, Z.; Lu, J.; Yu, J.J.; Zhao, J.; Zhang, B.; Zhang, Y. Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer. Cancer Res., 2018, 78(7), 1779-1791. doi: 10.1158/0008-5472.CAN-17-2460 PMID: 29374065Shank, J.J.; Yang, K.; Ghannam, J.; Cabrera, L.; Johnston, C.J.; Reynolds, R.K.; Buckanovich, R.J. Metformin targets ovarian cancer stem cells in vitro and in vivo. Gynecol. Oncol., 2012, 127(2), 390-397. doi: 10.1016/j.ygyno.2012.07.115 PMID: 22864111Brown, J.R.; Chan, D.K.; Shank, J.J.; Griffith, K.A.; Fan, H.; Szulawski, R.; Yang, K.; Reynolds, R.K.; Johnston, C.; McLean, K.; Uppal, S.; Liu, J.R.; Cabrera, L.; Taylor, S.E.; Orr, B.C.; Modugno, F.; Mehta, P.; Bregenzer, M.; Mehta, G.; Shen, H.; Coffman, L.; Buckanovich, R.J. Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer. JCI Insight, 2020, 5(11), e133247. doi: 10.1172/jci.insight.133247 PMID: 32369446Xie, Y.; Peng, Z.; Shi, M.; Ji, M.; Guo, H.; Shi, H. Metformin combined with p38 MAPK inhibitor improves cisplatin sensitivity in cisplatin-resistant ovarian cancer. Mol. Med. Rep., 2014, 10(5), 2346-2350. doi: 10.3892/mmr.2014.2490 PMID: 25118792Du, J.; Shi, H.; Ren, F.; Wang, J.; Wu, Q.; Li, X.; Zhang, R. Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cells. BMC Cancer, 2017, 17(1), 851. doi: 10.1186/s12885-017-3840-1 PMID: 29241458Liu, Y.; Feng, Y.; Liu, H.; Wu, J.; Tang, Y.; Wang, Q. Real-time assessment of platinum sensitivity of primary culture from a patient with ovarian cancer with extensive metastasis and the platinum sensitivity enhancing effect by metformin. Oncol. Lett., 2018, 16(4), 4253-4262. doi: 10.3892/ol.2018.9223 PMID: 30250536Lengyel, E.; Litchfield, L.M.; Mitra, A.K.; Nieman, K.M.; Mukherjee, A.; Zhang, Y.; Johnson, A.; Bradaric, M.; Lee, W.; Romero, I.L. Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models. Am. J. Obstet. Gynecol., 2015, 212(4), 479.e1-479.e10. doi: 10.1016/j.ajog.2014.10.026 PMID: 25446664Urpilainen, E.; Puistola, U.; Boussios, S.; Karihtala, P. Metformin and ovarian cancer: The evidence. Ann. Transl. Med., 2020, 8(24), 1711. doi: 10.21037/atm-20-1060 PMID: 33490223Bodmer, M.; Becker, C.; Meier, C.; Jick, S.S.; Meier, C.R. Use of metformin and the risk of ovarian cancer: A case-control analysis. Gynecol. Oncol., 2011, 123(2), 200-204. doi: 10.1016/j.ygyno.2011.06.038 PMID: 21802715Dilokthornsakul, P.; Chaiyakunapruk, N.; Termrungruanglert, W.; Pratoomsoot, C.; Saokeaw, S.; Sruamsiri, R. The effects of metformin on ovarian cancer: A systematic review. Int. J. Gynecol. Cancer, 2013, 23(9), 1544-1551. doi: 10.1097/IGC.0b013e3182a80a21 PMID: 24172091Tseng, C.H. Metformin reduces ovarian cancer risk in Taiwanese women with type 2 diabetes mellitus. Diabetes Metab. Res. Rev., 2015, 31(6), 619-626. doi: 10.1002/dmrr.2649 PMID: 25820555Shi, J.; Liu, B.; Wang, H.; Zhang, T.; Yang, L. Association of metformin use with ovarian cancer incidence and prognosis: A systematic review and meta-analysis. Int. J. Gynecol. Cancer, 2019, 29(1), 140-146. doi: 10.1136/ijgc-2018-000060 PMID: 30640696Najafi, F.; Rajati, F.; Sarokhani, D.; Bavandpour, M.; Moradinazar, M. The relationship between metformin consumption and cancer risk: An updated umbrella review of systematic reviews and meta-analyses. Int. J. Prev. Med., 2023, 14, 90. PMID: 37854987Romero, I.L.; McCormick, A.; McEwen, K.A.; Park, S.; Karrison, T.; Yamada, S.D.; Pannain, S.; Lengyel, E. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstet. Gynecol., 2012, 119(1), 61-67. doi: 10.1097/AOG.0b013e3182393ab3 PMID: 22183212Kumar, S.; Meuter, A.; Thapa, P.; Langstraat, C.; Giri, S.; Chien, J.; Rattan, R.; Cliby, W.; Shridhar, V. Metformin intake is associated with better survival in ovarian cancer. Cancer, 2013, 119(3), 555-562. doi: 10.1002/cncr.27706 PMID: 23208739Zhang, Z.J.; Li, S. The prognostic value of metformin for cancer patients with concurrent diabetes: A systematic review and meta‐analysis. Diabetes Obes. Metab., 2014, 16(8), 707-710. doi: 10.1111/dom.12267 PMID: 24460896Wang, S.B.; Lei, K.J.; Liu, J.P.; Jia, Y.M. Continuous use of metformin can improve survival in type 2 diabetic patients with ovarian cancer. Medicine, 2017, 96(29), e7605. doi: 10.1097/MD.0000000000007605 PMID: 28723808Noto, H.; Goto, A.; Tsujimoto, T.; Noda, M. Cancer risk in diabetic patients treated with metformin: A systematic review and meta-analysis. PLoS One, 2012, 7(3), e33411. doi: 10.1371/journal.pone.0033411 PMID: 22448244Park, J.Y.; Lim, M.C.; Baek, M.H.; Park, Y.H.; Kim, S. Impact of metformin on survival outcome in ovarian cancer: A nationwide population-based cohort study. J. Gynecol. Oncol., 2021, 32(4), e65. doi: 10.3802/jgo.2021.32.e65 PMID: 34085799Micha, J.P.; Rettenmaier, M.A.; Bohart, R.D.; Goldstein, B.H. A phase II, open-label, non-randomized, prospective study assessing paclitaxel, carboplatin and metformin in the treatment of advanced stage ovarian carcinoma. J. Gynecol. Oncol., 2023, 34(2), e15. doi: 10.3802/jgo.2023.34.e15 PMID: 36509462Broekman, K.E.; Hof, M.A.J.; Touw, D.J.; Gietema, J.A.; Nijman, H.W.; Lefrandt, J.D.; Reyners, A.K.L.; Jalving, M. Phase I study of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced epithelial ovarian cancer. Invest. New Drugs, 2020, 38(5), 1454-1462. doi: 10.1007/s10637-020-00920-7 PMID: 32146550Göbel, A.; Zinna, V.M.; Dell’Endice, S.; Jaschke, N.; Kuhlmann, J.D.; Wimberger, P.; Rachner, T.D. Anti-tumor effects of mevalonate pathway inhibition in ovarian cancer. BMC Cancer, 2020, 20(1), 703. doi: 10.1186/s12885-020-07164-x PMID: 32727400Schachter, M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: An update. Fundam. Clin. Pharmacol., 2005, 19(1), 117-125. doi: 10.1111/j.1472-8206.2004.00299.x PMID: 15660968Matsuura, M.; Suzuki, T.; Suzuki, M.; Tanaka, R.; Ito, E.; Saito, T. Statin-mediated reduction of osteopontin expression induces apoptosis and cell growth arrest in ovarian clear cell carcinoma. Oncol. Rep., 2011, 25(1), 41-47. PMID: 21109955Robinson, E.; Nandi, M.; Wilkinson, L.L.; Arrowsmith, D.M.; Curtis, A.D.M.; Richardson, A. Preclinical evaluation of statins as a treatment for ovarian cancer. Gynecol. Oncol., 2013, 129(2), 417-424. doi: 10.1016/j.ygyno.2013.02.003 PMID: 23402903Kobayashi, Y.; Kashima, H.; Wu, R.C.; Jung, J.G.; Kuan, J.C.; Gu, J.; Xuan, J.; Sokoll, L.; Visvanathan, K.; Shih, I.M.; Wang, T.L. Mevalonate pathway antagonist suppresses formation of serous tubal intraepithelial carcinoma and ovarian carcinoma in mouse models. Clin. Cancer Res., 2015, 21(20), 4652-4662. doi: 10.1158/1078-0432.CCR-14-3368 PMID: 26109099Zeybek, B.; Costantine, M.; Kilic, G.S.; Borahay, M.A. Therapeutic roles of statins in gynecology and obstetrics: The current evidence. Reprod. Sci., 2018, 25(6), 802-817. doi: 10.1177/1933719117750751 PMID: 29320955Stine, J.E.; Guo, H.; Sheng, X.; Han, X.; Schointuch, M.N.; Gilliam, T.P.; Gehrig, P.A.; Zhou, C.; Bae-Jump, V.L. The HMG-CoA reductase inhibitor, simvastatin, exhibits anti-metastatic and anti-tumorigenic effects in ovarian cancer. Oncotarget, 2016, 7(1), 946-960. doi: 10.18632/oncotarget.5834 PMID: 26503475Lavie, O.; Pinchev, M.; Rennert, H.S.; Segev, Y.; Rennert, G. The effect of statins on risk and survival of gynecological malignancies. Gynecol. Oncol., 2013, 130(3), 615-619. doi: 10.1016/j.ygyno.2013.05.025 PMID: 23718932Harding, B.N.; Delaney, J.A.; Urban, R.R.; Weiss, N.S. Use of statin medications following diagnosis in relation to survival among women with ovarian cancer. Cancer Epidemiol. Biomarkers Prev., 2019, 28(7), 1127-1133. doi: 10.1158/1055-9965.EPI-18-1194 PMID: 31064757Couttenier, A.; Lacroix, O.; Vaes, E.; Cardwell, C.R.; De Schutter, H.; Robert, A. Statin use is associated with improved survival in ovarian cancer: A retrospective population-based study. PLoS One, 2017, 12(12), e0189233. doi: 10.1371/journal.pone.0189233 PMID: 29261726Majidi, A.; Na, R.; Jordan, S.J.; De Fazio, A.; Webb, P.M. Statin use and survival following a diagnosis of ovarian cancer: A prospective observational study. Int. J. Cancer, 2021, 148(7), 1608-1615. doi: 10.1002/ijc.33333 PMID: 33034053Feng, J.L.; Dixon-Suen, S.C.; Jordan, S.J.; Webb, P.M. Statin use and survival among women with ovarian cancer: An Australian national data-linkage study. Br. J. Cancer, 2021, 125(5), 766-771. doi: 10.1038/s41416-021-01460-4 PMID: 34135470Xie, W.; Ning, L.; Huang, Y.; Liu, Y.; Zhang, W.; Hu, Y.; Lang, J.; Yang, J. Statin use and survival outcomes in endocrine-related gynecologic cancers: A systematic review and meta-analysis. Oncotarget, 2017, 8(25), 41508-41517. doi: 10.18632/oncotarget.17242 PMID: 28489569Li, X.; Zhou, J. Impact of postdiagnostic statin use on ovarian cancer mortality: A systematic review and meta‐analysis of observational studies. Br. J. Clin. Pharmacol., 2018, 84(6), 1109-1120. doi: 10.1111/bcp.13559 PMID: 29453799Wang, Y.; Ren, F.; Song, Z.; Chen, P.; Liu, S.; Ouyang, L. Statin use and the risk of ovarian and endometrial cancers: A meta-analysis. BMC Cancer, 2019, 19(1), 730. doi: 10.1186/s12885-019-5954-0 PMID: 31340777Desai, P.; Wallace, R.; Anderson, M.L.; Howard, B.V.; Ray, R.M.; Wu, C.; Safford, M.; Martin, L.W.; Rohan, T.; Manson, J.E.; Simon, M.S. An analysis of the association between statin use and risk of endometrial and ovarian cancers in the Women’s Health Initiative. Gynecol. Oncol., 2018, 148(3), 540-546. doi: 10.1016/j.ygyno.2018.01.006 PMID: 29422345Kobayashi, Y.; Takeda, T.; Kunitomi, H.; Chiwaki, F.; Komatsu, M.; Nagai, S.; Nogami, Y.; Tsuji, K.; Masuda, K.; Ogiwara, H.; Sasaki, H.; Banno, K.; Aoki, D. Response predictive markers and synergistic agents for drug repositioning of statins in ovarian cancer. Pharmaceuticals, 2022, 15(2), 124. doi: 10.3390/ph15020124 PMID: 35215239Xia, L.; Ding, S.; Wang, X.; Zhang, X.; Zhu, L.; Zhang, H.; Li, H. Advances in ovarian cancer treatment using a combination of statins with other drugs. Front. Pharmacol., 2023, 13, 1048484. doi: 10.3389/fphar.2022.1048484 PMID: 36686716Luckman, S.P.; Hughes, D.E.; Coxon, F.P.; Russell, R.G.G.; Rogers, M.J.; Rogers, M.J. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J. Bone Miner. Res., 1998, 13(4), 581-589. doi: 10.1359/jbmr.1998.13.4.581 PMID: 9556058Holen, I.; Coleman, R.E. Anti-tumour activity of bisphosphonates in preclinical models of breast cancer. Breast Cancer Res., 2010, 12(6), 214. doi: 10.1186/bcr2769 PMID: 21176176Clezardin, P. Potential anticancer properties of bisphosphonates: Insights from preclinical studies. Anticancer. Agents Med. Chem., 2012, 12(2), 102-113. doi: 10.2174/187152012799014977 PMID: 21864232Koul, H.K.; Koul, S.; Meacham, R.B. New role for an established drug? Bisphosphonates as potential anticancer agents. Prostate Cancer Prostatic Dis., 2012, 15(2), 111-119. doi: 10.1038/pcan.2011.41 PMID: 21876554Goldvaser, H.; Amir, E. Role of bisphosphonates in breast cancer therapy. Curr. Treat. Options Oncol., 2019, 20(4), 26. doi: 10.1007/s11864-019-0623-8 PMID: 30874905Dionísio, M.R.; Mansinho, A.; Abreu, C.; Cavaco-Silva, J.; Casimiro, S.; Costa, L. Clinical and translational pharmacology of drugs for the prevention and treatment of bone metastases and cancer‐induced bone loss. Br. J. Clin. Pharmacol., 2019, 85(6), 1114-1124. doi: 10.1111/bcp.13852 PMID: 30601585Hadji, P.; Body, J.J.; Aapro, M.S.; Brufsky, A.; Coleman, R.E.; Guise, T.; Lipton, A.; Tubiana-Hulin, M. Practical guidance for the management of aromatase inhibitor-associated bone loss. Ann. Oncol., 2008, 19(8), 1407-1416. doi: 10.1093/annonc/mdn164 PMID: 18448451Wong, M.H.; Stockler, M.R.; Pavlakis, N. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst. Rev., 2012, 2(2), CD003474. PMID: 22336790Mathew, A.; Brufsky, A. Bisphosphonates in breast cancer. Int. J. Cancer, 2015, 137(4), 753-764. doi: 10.1002/ijc.28965 PMID: 24824552Takahashi, S. Management of cancer treatment-induced bone loss (CTIBL) in patients with breast cancer or prostate cancer. J. Bone Miner. Metab., 2023, 41(3), 307-316. doi: 10.1007/s00774-023-01414-1 PMID: 37036530Morgan, G.J.; Davies, F.E.; Gregory, W.M.; Cocks, K.; Bell, S.E.; Szubert, A.J.; Navarro-Coy, N.; Drayson, M.T.; Owen, R.G.; Feyler, S.; Ashcroft, A.J.; Ross, F.; Byrne, J.; Roddie, H.; Rudin, C.; Cook, G.; Jackson, G.H.; Child, J.A. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): A randomised controlled trial. Lancet, 2010, 376(9757), 1989-1999. doi: 10.1016/S0140-6736(10)62051-X PMID: 21131037Wilson, C.; Ottewell, P.; Coleman, R.E.; Holen, I. The differential anti-tumour effects of zoledronic acid in breast cancer - evidence for a role of the activin signaling pathway. BMC Cancer, 2015, 15(1), 55. doi: 10.1186/s12885-015-1066-7 PMID: 25884855Fragni, M.; Bonini, S.A.; Bettinsoli, P.; Bodei, S.; Generali, D.; Bottini, A.; Spano, P.F.; Memo, M.; Sigala, S. The miR-21/PTEN/Akt signaling pathway is involved in the anti-tumoral effects of zoledronic acid in human breast cancer cell lines. Naunyn Schmiedebergs Arch. Pharmacol., 2016, 389(5), 529-538. doi: 10.1007/s00210-016-1224-8 PMID: 26905520Seto, H.; Kita, T.; Hirata, J.; Kikuchi, Y.; Kudoh, K. Inhibitory effects of bisphosphonates on the proliferation of human ovarian cancer cell lines and the mechanism. Med. Chem., 2006, 2(3), 223-226. doi: 10.2174/157340606776930727 PMID: 16948467Kobayashi, Y.; Kashima, H.; Rahmanto, Y.S.; Banno, K.; Yu, Y.; Matoba, Y.; Watanabe, K.; Iijima, M.; Takeda, T.; Kunitomi, H.; Iida, M.; Adachi, M.; Nakamura, K.; Tsuji, K.; Masuda, K.; Nomura, H.; Tominaga, E.; Aoki, D. Drug repositioning of mevalonate pathway inhibitors as antitumor agents for ovarian cancer. Oncotarget, 2017, 8(42), 72147-72156. doi: 10.18632/oncotarget.20046 PMID: 29069775Atmaca, H.; Gorumlu, G.; Karaca, B.; Degirmenci, M.; Tunali, D.; Cirak, Y.; Purcu, D.U.; Uzunoglu, S.; Karabulut, B.; Sanli, U.A.; Uslu, R. Combined gossypol and zoledronic acid treatment results in synergistic induction of cell death and regulates angiogenic molecules in ovarian cancer cells. Eur. Cytokine Netw., 2009, 20(3), 121-130. doi: 10.1684/ecn.2009.0159 PMID: 19825521Karabulut, B.; Karaca, B.; Varol, U.; Muslu, U.; Cakar, B.; Atmaca, H.; Kısım, A.; Uzunoglu, S.; Uslu, R. Enhancing cytotoxic and apoptotic effect in OVCAR-3 and MDAH-2774 cells with all-trans retinoic acid and zoledronic acid: A paradigm of synergistic molecular targeting treatment for ovarian cancer. J. Exp. Clin. Cancer Res., 2010, 29(1), 102. doi: 10.1186/1756-9966-29-102 PMID: 20673323Abdullah, M.I.; Abed, M.N.; Richardson, A. Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells. Sci. Rep., 2017, 7(1), 8090. doi: 10.1038/s41598-017-08649-9 PMID: 28808351Knight, L.A.; Kurbacher, C.M.; Glaysher, S.; Fernando, A.; Reichelt, R.; Dexel, S.; Reinhold, U.; Cree, I.A. Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay. BMC Cancer, 2009, 9(1), 38. doi: 10.1186/1471-2407-9-38 PMID: 19175937Muinelo-Romay, L.; Garcia, D.; Alonso-Alconada, L.; Vieito, M.; Carmona, M.; Martínez, N.; Aguín, S.; Abal, M.; López-López, R. Zoledronic acid as an antimetastatic agent for different human tumor cell lines. Anticancer Res., 2013, 33(12), 5295-5300. PMID: 24324062Hashimoto, K.; Morishige, K.; Sawada, K.; Tahara, M.; Kawagishi, R.; Ikebuchi, Y.; Sakata, M.; Tasaka, K.; Murata, Y. Alendronate inhibits intraperitoneal dissemination in in vivo ovarian cancer model. Cancer Res., 2005, 65(2), 540-545. doi: 10.1158/0008-5472.540.65.2 PMID: 15695397Oxford, G.; Theodorescu, D. Ras superfamily monomeric G proteins in carcinoma cell motility. Cancer Lett., 2003, 189(2), 117-128. doi: 10.1016/S0304-3835(02)00510-4 PMID: 12490304Rennert, G.; Rennert, H.S.; Pinchev, M.; Lavie, O. The effect of bisphosphonates on the risk of endometrial and ovarian malignancies. Gynecol. Oncol., 2014, 133(2), 309-313. doi: 10.1016/j.ygyno.2014.02.014 PMID: 24556062Tuesley, K.M.; Webb, P.M.; Protani, M.M.; Spilsbury, K.; Pearson, S.A.; Coory, M.D.; Donovan, P.; Steer, C.; Stewart, L.M.; Pandeya, N.; Jordan, S.J. Nitrogen-based bisphosphonate use and ovarian cancer risk in women aged 50 years and older. J. Natl. Cancer Inst., 2022, 114(6), 878-884. doi: 10.1093/jnci/djac050 PMID: 35262727Bae, Y.S.; Chang, J.; Park, S.M. Oral bisphosphonate use and the risk of female breast, ovarian, and cervical cancer: A nationwide population-based cohort study. Arch. Osteoporos., 2019, 14(1), 41. doi: 10.1007/s11657-019-0588-z PMID: 30888545Zhang, X.; Zhang, Y.; Li, B.; Fan, B.; Zhao, Y.; Yang, S. Risk reduction of endometrial and ovarian cancer after bisphosphonates use: A meta-analysis. Gynecol. Oncol., 2018, 150(3), 509-514. doi: 10.1016/j.ygyno.2018.06.012 PMID: 29960711Chai, E.Z.P.; Siveen, K.S.; Shanmugam, M.K.; Arfuso, F.; Sethi, G. Analysis of the intricate relationship between chronic inflammation and cancer. Biochem. J., 2015, 468(1), 1-15. doi: 10.1042/BJ20141337 PMID: 25940732Trabert, B.; Pinto, L.; Hartge, P.; Kemp, T.; Black, A.; Sherman, M.E.; Brinton, L.A.; Pfeiffer, R.M.; Shiels, M.S.; Chaturvedi, A.K.; Hildesheim, A.; Wentzensen, N. Pre-diagnostic serum levels of inflammation markers and risk of ovarian cancer in the prostate, lung, colorectal and ovarian cancer (PLCO) screening trial. Gynecol. Oncol., 2014, 135(2), 297-304. doi: 10.1016/j.ygyno.2014.08.025 PMID: 25158036Zhang, Z.; Chen, F.; Shang, L. Advances in antitumor effects of NSAIDs. Cancer Manag. Res., 2018, 10, 4631-4640. doi: 10.2147/CMAR.S175212 PMID: 30410398Thorat, M.A.; Cuzick, J. Role of aspirin in cancer prevention. Curr. Oncol. Rep., 2013, 15(6), 533-540. doi: 10.1007/s11912-013-0351-3 PMID: 24114189Guo, J.; Zhu, Y.; Yu, L.; Li, Y.; Guo, J.; Cai, J.; Liu, L.; Wang, Z. Aspirin inhibits tumor progression and enhances cisplatin sensitivity in epithelial ovarian cancer. PeerJ, 2021, 9, e11591. doi: 10.7717/peerj.11591 PMID: 34414020Merritt, M.A.; Rice, M.S.; Barnard, M.E.; Hankinson, S.E.; Matulonis, U.A.; Poole, E.M.; Tworoger, S.S. Pre-diagnosis and post-diagnosis use of common analgesics and ovarian cancer prognosis (NHS/NHSII): A cohort study. Lancet Oncol., 2018, 19(8), 1107-1116. doi: 10.1016/S1470-2045(18)30373-5 PMID: 30029888Verdoodt, F.; Kjaer, S.K.; Dehlendorff, C.; Friis, S. Aspirin use and ovarian cancer mortality in a Danish nationwide cohort study. Br. J. Cancer, 2018, 118(4), 611-615. doi: 10.1038/bjc.2017.449 PMID: 29315293Dixon, S.C.; Nagle, C.M.; Wentzensen, N.; Trabert, B.; Beeghly-Fadiel, A.; Schildkraut, J.M.; Moysich, K.B.; deFazio, A.; Risch, H.A.; Rossing, M.A.; Doherty, J.A.; Wicklund, K.G.; Goodman, M.T.; Modugno, F.; Ness, R.B.; Edwards, R.P.; Jensen, A.; Kjær, S.K.; Høgdall, E.; Berchuck, A.; Cramer, D.W.; Terry, K.L.; Poole, E.M.; Bandera, E.V.; Paddock, L.E.; Anton-Culver, H.; Ziogas, A.; Menon, U.; Gayther, S.A.; Ramus, S.J.; Gentry-Maharaj, A.; Pearce, C.L.; Wu, A.H.; Pike, M.C.; Webb, P.M. Use of common analgesic medications and ovarian cancer survival: Results from a pooled analysis in the Ovarian Cancer Association Consortium. Br. J. Cancer, 2017, 116(9), 1223-1228. doi: 10.1038/bjc.2017.68 PMID: 28350790Trabert, B.; Poole, E.M.; White, E.; Visvanathan, K.; Adami, H.O.; Anderson, G.L.; Brasky, T.M.; Brinton, L.A.; Fortner, R.T.; Gaudet, M.; Hartge, P.; Hoffman-Bolton, J.; Jones, M.; Lacey, J.V., Jr; Larsson, S.C.; Mackenzie, G.G.; Schouten, L.J.; Sandler, D.P.; O’Brien, K.; Patel, A.V.; Peters, U.; Prizment, A.; Robien, K.; Setiawan, V.W.; Swerdlow, A.; van den Brandt, P.A.; Weiderpass, E.; Wilkens, L.R.; Wolk, A.; Wentzensen, N.; Tworoger, S.S. Analgesic use and ovarian cancer risk: An analysis in the ovarian cancer cohort consortium. J. Natl. Cancer Inst., 2019, 111(2), 137-145. doi: 10.1093/jnci/djy100 PMID: 29860330Hurwitz, L.M.; Pinsky, P.F.; Huang, W.Y.; Freedman, N.D.; Trabert, B. Aspirin use and ovarian cancer risk using extended follow-up of the PLCO Cancer Screening Trial. Gynecol. Oncol., 2020, 159(2), 522-526. doi: 10.1016/j.ygyno.2020.08.038 PMID: 32919779Man, X.; Wang, B.; Tan, Y.; Yang, X.; Zhang, S. aspirin use and mortality in women with ovarian cancer: A meta-analysis. Front. Oncol., 2021, 10, 575831. doi: 10.3389/fonc.2020.575831 PMID: 33598421Wield, A.M.; Walsh, C.S.; Rimel, B.J.; Cass, I.; Karlan, B.Y.; Li, A.J. Aspirin use correlates with survival in women with clear cell ovarian cancer. Gynecol. Oncol. Rep., 2018, 25, 78-81. doi: 10.1016/j.gore.2018.06.004 PMID: 29922710Tsubamoto, H.; Ueda, T.; Inoue, K.; Sakata, K.; Shibahara, H.; Sonoda, T. Repurposing itraconazole as an anticancer agent. Oncol. Lett., 2017, 14(2), 1240-1246. doi: 10.3892/ol.2017.6325 PMID: 28789339Pounds, R.; Leonard, S.; Dawson, C.; Kehoe, S. Repurposing itraconazole for the treatment of cancer. Oncol. Lett., 2017, 14(3), 2587-2597. doi: 10.3892/ol.2017.6569 PMID: 28927025Li, C.L.; Fang, Z.X.; Wu, Z.; Hou, Y.Y.; Wu, H.T.; Liu, J. Repurposed itraconazole for use in the treatment of malignancies as a promising therapeutic strategy. Biomed. Pharmacother., 2022, 154, 113616. doi: 10.1016/j.biopha.2022.113616 PMID: 36055112Gupta, S.; Kim, J.; Gollapudi, S. Reversal of daunorubicin resistance in P388/ADR cells by itraconazole. J. Clin. Invest., 1991, 87(4), 1467-1469. doi: 10.1172/JCI115154 PMID: 1849151Kurosawa, M.; Okabe, M.; Hara, N.; Kawamura, K.; Suzuki, S.; Sakurada, K.; Asaka, M. Reversal effect of itraconazole on adriamycin and etoposide resistance in human leukemia cells. Ann. Hematol., 1996, 72(1), 17-21. doi: 10.1007/BF00663011 PMID: 8605275Takara, K.; Tanigawara, Y.; Komada, F.; Nishiguchi, K.; Sakaeda, T.; Okumura, K. Cellular pharmacokinetic aspects of reversal effect of itraconazole on P-glycoprotein-mediated resistance of anticancer drugs. Biol. Pharm. Bull., 1999, 22(12), 1355-1359. doi: 10.1248/bpb.22.1355 PMID: 10746169Chong, C.R.; Xu, J.; Lu, J.; Bhat, S.; Sullivan, D.J., Jr; Liu, J.O. Inhibition of angiogenesis by the antifungal drug itraconazole. ACS Chem. Biol., 2007, 2(4), 263-270. doi: 10.1021/cb600362d PMID: 17432820Choi, C.H.; Ryu, J.Y.; Cho, Y.J.; Jeon, H.K.; Choi, J.J.; Ylaya, K.; Lee, Y.Y.; Kim, T.J.; Chung, J.Y.; Hewitt, S.M.; Kim, B.G.; Bae, D.S.; Lee, J.W. The anti-cancer effects of itraconazole in epithelial ovarian cancer. Sci. Rep., 2017, 7(1), 6552. doi: 10.1038/s41598-017-06510-7 PMID: 28747628Tsubamoto, H.; Sonoda, T.; Yamasaki, M.; Inoue, K. Impact of combination chemotherapy with itraconazole on survival for patients with recurrent or persistent ovarian clear cell carcinoma. Anticancer Res., 2014, 34(4), 2007-2014. PMID: 24692739Tsubamoto, H.; Sonoda, T.; Yamasaki, M.; Inoue, K. Impact of combination chemotherapy with itraconazole on survival of patients with refractory ovarian cancer. Anticancer Res., 2014, 34(5), 2481-2487. PMID: 24778064Marastoni, S.; Madariaga, A.; Pesic, A.; Nair, S.N.; Li, Z.J.; Shalev, Z.; Ketela, T.; Colombo, I.; Mandilaras, V.; Cabanero, M.; Bruce, J.P.; Li, X.; Garg, S.; Wang, L.; Chen, E.X.; Gill, S.; Dhani, N.C.; Zhang, W.; Pintilie, M.; Bowering, V.; Koritzinsky, M.; Rottapel, R.; Wouters, B.G.; Oza, A.M.; Joshua, A.M.; Lheureux, S. Repurposing itraconazole and hydroxychloroquine to target lysosomal homeostasis in epithelial ovarian cancer. Cancer Research Communications, 2022, 2(5), 293-306. doi: 10.1158/2767-9764.CRC-22-0037 PMID: 36875717Laing, R.; Gillan, V.; Devaney, E. Ivermectin - old drug, new tricks? Trends Parasitol., 2017, 33(6), 463-472. doi: 10.1016/j.pt.2017.02.004 PMID: 28285851Juarez, M.; Schcolnik-Cabrera, A.; Dueñas-Gonzalez, A. The multitargeted drug ivermectin: From an antiparasitic agent to a repositioned cancer drug. Am. J. Cancer Res., 2018, 8(2), 317-331. PMID: 29511601Tang, M.; Hu, X.; Wang, Y.; Yao, X.; Zhang, W.; Yu, C.; Cheng, F.; Li, J.; Fang, Q. Ivermectin, a potential anticancer drug derived from an antiparasitic drug. Pharmacol. Res., 2021, 163, 105207. doi: 10.1016/j.phrs.2020.105207 PMID: 32971268Hashimoto, H.; Messerli, S.M.; Sudo, T.; Maruta, H. Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines. Drug Discov. Ther., 2009, 3(6), 243-246. PMID: 22495656Li, N.; Zhan, X. Anti-parasite drug ivermectin can suppress ovarian cancer by regulating lncRNA-EIF4A3-mRNA axes. EPMA J., 2020, 11(2), 289-309. doi: 10.1007/s13167-020-00209-y PMID: 32549918Kodama, M.; Kodama, T.; Newberg, J.Y.; Katayama, H.; Kobayashi, M.; Hanash, S.M.; Yoshihara, K.; Wei, Z.; Tien, J.C.; Rangel, R.; Hashimoto, K.; Mabuchi, S.; Sawada, K.; Kimura, T.; Copeland, N.G.; Jenkins, N.A. In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer. Proc. Natl. Acad. Sci., 2017, 114(35), E7301-E7310. doi: 10.1073/pnas.1705441114 PMID: 28811376Zhan, X.; Li, N. The anti-cancer effects of anti-parasite drug ivermectin in ovarian cancer. In: Ovarian Cancer - Updates in Tumour Biology and Therapeutics; IntechOpen, 2021. doi: 10.5772/intechopen.95556Zhang, X.; Qin, T.; Zhu, Z.; Hong, F.; Xu, Y.; Zhang, X.; Xu, X.; Ma, A. Ivermectin augments the in vitro and in vivo efficacy of cisplatin in epithelial ovarian cancer by suppressing Akt/mTOR signaling. Am. J. Med. Sci., 2020, 359(2), 123-129. doi: 10.1016/j.amjms.2019.11.001 PMID: 32039764Xia, Y.; Chang, T.; Wang, Y.; Liu, Y.; Li, W.; Li, M.; Fan, H.Y. YAP promotes ovarian cancer cell tumorigenesis and is indicative of a poor prognosis for ovarian cancer patients. PLoS One, 2014, 9(3), e91770. doi: 10.1371/journal.pone.0091770 PMID: 24622501Nishio, M.; Sugimachi, K.; Goto, H.; Wang, J.; Morikawa, T.; Miyachi, Y.; Takano, Y.; Hikasa, H.; Itoh, T.; Suzuki, S.O.; Kurihara, H.; Aishima, S.; Leask, A.; Sasaki, T.; Nakano, T.; Nishina, H.; Nishikawa, Y.; Sekido, Y.; Nakao, K.; Shin-ya, K.; Mimori, K.; Suzuki, A. Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b -deficient mice. Proc. Natl. Acad. Sci., 2016, 113(1), E71-E80. doi: 10.1073/pnas.1517188113 PMID: 26699479Nambara, S.; Masuda, T.; Nishio, M.; Kuramitsu, S.; Tobo, T.; Ogawa, Y.; Hu, Q.; Iguchi, T.; Kuroda, Y.; Ito, S.; Eguchi, H.; Sugimachi, K.; Saeki, H.; Oki, E.; Maehara, Y.; Suzuki, A.; Mimori, K. Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer. Oncotarget, 2017, 8(64), 107666-107677. doi: 10.18632/oncotarget.22587 PMID: 29296196Bruno, C.; Carocci, A.; Catalano, A.; Cavalluzzi, M.M.; Corbo, F.; Franchini, C.; Lentini, G.; Tortorella, V. Facile, alternative route to Lubeluzole, its enantiomer, and the racemate. Chirality, 2006, 18(4), 227-231. doi: 10.1002/chir.20240 PMID: 16521088Grand, B.L.; Dordain-Maffre, M.; John, G.W. Lubeluzole‐induced prolongation of cardiac action potential in rabbit Purkinje fibres. Fundam. Clin. Pharmacol., 2000, 14(2), 159-162. doi: 10.1111/j.1472-8206.2000.tb00405.x PMID: 10796064Gandolfo, C.; Sandercock, P.; Conti, M. Lubeluzole for acute ischaemic stroke. Cochrane Database Syst. Rev., 2002, 1(1), CD001924. PMID: 11869612Desaphy, J.F.; Carbonara, R.; Costanza, T.; Lentini, G.; Cavalluzzi, M.M.; Bruno, C.; Franchini, C.; Camerino, D.C. Molecular dissection of lubeluzole use-dependent block of voltage-gated sodium channels discloses new therapeutic potentials. Mol. Pharmacol., 2013, 83(2), 406-415. doi: 10.1124/mol.112.080804 PMID: 23175529Bruno, C.; Cavalluzzi, M.M.; Rusciano, M.R.; Lovece, A.; Carrieri, A.; Pracella, R.; Giannuzzi, G.; Polimeno, L.; Viale, M.; Illario, M.; Franchini, C.; Lentini, G. The chemosensitizing agent lubeluzole binds calmodulin and inhibits Ca2+/calmodulin-dependent kinase II. Eur. J. Med. Chem., 2016, 116, 36-45. doi: 10.1016/j.ejmech.2016.03.045 PMID: 27043269Gualdani, R.; Cavalluzzi, M.M.; Tadini-Buoninsegni, F.; Convertino, M.; Gailly, P.; Stary-Weinzinger, A.; Lentini, G. Molecular insights into hERG potassium channel blockade by lubeluzole. Cell. Physiol. Biochem., 2018, 45(6), 2233-2245. doi: 10.1159/000488169 PMID: 29550817Cavalluzzi, M.M.; Viale, M.; Bruno, C.; Carocci, A.; Catalano, A.; Carrieri, A.; Franchini, C.; Lentini, G. A convenient synthesis of lubeluzole and its enantiomer: Evaluation as chemosensitizing agents on human ovarian adenocarcinoma and lung carcinoma cells. Bioorg. Med. Chem. Lett., 2013, 23(17), 4820-4823. doi: 10.1016/j.bmcl.2013.06.077 PMID: 23886686Cavalluzzi, M.M.; Budriesi, R.; De Salvia, M.A.; Quintieri, L.; Piarulli, M.; Milani, G.; Gualdani, R.; Micucci, M.; Corazza, I.; Rosato, A.; Viale, M.; Caputo, L.; Franchini, C.; Lentini, G. Lubeluzole: From anti-ischemic drug to preclinical antidiarrheal studies. Pharmacol. Rep., 2021, 73(1), 172-184. doi: 10.1007/s43440-020-00167-2 PMID: 33074530Viale, M.; Lentini, G.; Gangemi, R.; Castagnola, P.; Milani, G.; Ravera, S.; Bertola, N.; Carrieri, A.; Cavalluzzi, M. Lubeluzole repositioning as chemosensitizing agent on multidrug-resistant human ovarian A2780/DX3 cancer cells. Molecules, 2022, 27(22), 7870. doi: 10.3390/molecules27227870 PMID: 36431971Wright, C.; Moore, R.D. Disulfiram treatment of alcoholism. Am. J. Med., 1990, 88(6), 647-655. doi: 10.1016/0002-9343(90)90534-K PMID: 2189310Interventions For Addiction. Medication for Cravings in Substance Use Disorders; Elsevier Inc, 2013.Swift, R.; Leggio, L. Adjunctive pharmacotherapy in the treatment of alcohol and drug dependence. In: Evidence-Based Addiction Treatment; Miller, P.M., Ed.; Academic Press, 2009. doi: 10.1016/B978-0-12-374348-0.00015-XJiao, Y.; Hannafon, B.N.; Ding, W.Q. Disulfiram’s anticancer activity: Evidence and mechanisms. Anticancer. Agents Med. Chem., 2016, 16, 1378-1384.Wang, L.; Yu, Y.; Zhou, C.; Wan, R.; Li, Y. Anticancer effects of disulfiram: A systematic review of in vitro, animal, and human studies. Syst. Rev., 2022, 11(1), 109. doi: 10.1186/s13643-021-01858-4 PMID: 35655266Zhang, S.; Zong, Y.; Chen, L.; Li, Q.; Li, Z.; Meng, R. The immunomodulatory function and antitumor effect of disulfiram: Paving the way for novel cancer therapeutics. Discov. Oncol., 2023, 14(1), 103. doi: 10.1007/s12672-023-00729-9 PMID: 37326784Guo, F.; Yang, Z.; Kulbe, H.; Albers, A.E.; Sehouli, J.; Kaufmann, A.M. Inhibitory effect on ovarian cancer ALDH+ stem-like cells by Disulfiram and Copper treatment through ALDH and ROS modulation. Biomed. Pharmacother., 2019, 118, 109371. doi: 10.1016/j.biopha.2019.109371 PMID: 31545281Rezk, Y.A.; Yang, K.; Bai, S.; Mclean, K.; Johnston, C.; Reynolds, R.K.; Buckanovich, R.J. Disulfiram’s antineoplastic effects on ovarian cancer. J. Cancer Ther., 2015, 6(14), 1196-1205. doi: 10.4236/jct.2015.614130Gan, Y.; Liu, T.; Feng, W.; Wang, L.; Li, L.; Ning, Y. Drug repositioning of disulfiram induces endometrioid epithelial ovarian cancer cell death via the both apoptosis and cuproptosis pathways. Oncol. Res., 2023, 31(3), 333-343. doi: 10.32604/or.2023.028694 PMID: 37305383Tsvetkov, P.; Coy, S.; Petrova, B.; Dreishpoon, M.; Verma, A.; Abdusamad, M.; Rossen, J.; Joesch-Cohen, L.; Humeidi, R.; Spangler, R.D.; Eaton, J.K.; Frenkel, E.; Kocak, M.; Corsello, S.M.; Lutsenko, S.; Kanarek, N.; Santagata, S.; Golub, T.R. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science, 2022, 375(6586), 1254-1261. doi: 10.1126/science.abf0529 PMID: 35298263Tang, B.; Wu, M.; Zhang, L.; Jian, S.; Lv, S.; Lin, T.; Zhu, S.; Liu, L.; Wang, Y.; Yi, Z.; Jiang, F. Combined treatment of disulfiram with PARP inhibitors suppresses ovarian cancer. Front. Oncol., 2023, 13, 1154073. doi: 10.3389/fonc.2023.1154073 PMID: 37143950Wang, N.; Ma, T.; Yu, B. Targeting epigenetic regulators to overcome drug resistance in cancers. Signal Transduct. Target. Ther., 2023, 8(1), 69. doi: 10.1038/s41392-023-01341-7 PMID: 36797239Wang, Y.; Huang, Z.; Li, B.; Liu, L.; Huang, C. The emerging roles and therapeutic implications of epigenetic modifications in ovarian cancer. Front. Endocrinol., 2022, 13, 863541. doi: 10.3389/fendo.2022.863541 PMID: 35620395Asadollahi, R.; Hyde, C.A.C.; Zhong, X.Y. Epigenetics of ovarian cancer: From the lab to the clinic. Gynecol. Oncol., 2010, 118(1), 81-87. doi: 10.1016/j.ygyno.2010.03.015 PMID: 20421130Matthews, B.; Bowden, N.; Wong-Brown, M. Epigenetic mechanisms and therapeutic targets in chemoresistant high-grade serous ovarian cancer. Cancers, 2021, 13(23), 5993. doi: 10.3390/cancers13235993 PMID: 34885103Jurkowska, R.Z.; Jurkowski, T.P.; Jeltsch, A. Structure and function of mammalian DNA methyltransferases. ChemBioChem, 2011, 12(2), 206-222. doi: 10.1002/cbic.201000195 PMID: 21243710Sato, T.; Issa, J.P.J.; Kropf, P. DNA hypomethylating drugs in cancer therapy. Cold Spring Harb. Perspect. Med., 2017, 7(5), a026948. doi: 10.1101/cshperspect.a026948 PMID: 28159832Smith, H.J.; Straughn, J.M.; Buchsbaum, D.J.; Arend, R.C. Epigenetic therapy for the treatment of epithelial ovarian cancer: A clinical review. Gynecol. Oncol. Rep., 2017, 20, 81-86. doi: 10.1016/j.gore.2017.03.007 PMID: 28378010Rauscher, S.; Greil, R.; Geisberger, R. Re-sensitizing tumor cells to cancer drugs with epigenetic regulators. Curr. Cancer Drug Targets, 2021, 21(4), 353-359. doi: 10.2174/1568009620666210108102723 PMID: 33423645Kim, H-J.; Bae, S.C. Histone deacetylase inhibitors: Molecular mechanisms of action and clinical trials as anti-cancer drugs. Am. J. Transl. Res., 2011, 3(2), 166-179. PMID: 21416059Moufarrij, S.; Dandapani, M.; Arthofer, E.; Gomez, S.; Srivastava, A.; Lopez-Acevedo, M.; Villagra, A.; Chiappinelli, K.B. Epigenetic therapy for ovarian cancer: Promise and progress. Clin. Epigenetics, 2019, 11(1), 7. doi: 10.1186/s13148-018-0602-0 PMID: 30646939Armando, R.G.; Mengual, G.D.L.; Gomez, D.E. New drugs are not enough-drug repositioning in oncology: An update. Int. J. Oncol., 2020, 56(3), 651-684. doi: 10.3892/ijo.2020.4966 PMID: 32124955Moreira-Silva, F.; Camilo, V.; Gaspar, V.; Mano, J.F.; Henrique, R.; Jerónimo, C. Repurposing old drugs into new epigenetic inhibitors: Promising candidates for cancer treatment? Pharmaceutics, 2020, 12(5), 410. doi: 10.3390/pharmaceutics12050410 PMID: 32365701Correia, A.S.; Gärtner, F.; Vale, N. Drug combination and repurposing for cancer therapy: The example of breast cancer. Heliyon, 2021, 7(1), e05948. doi: 10.1016/j.heliyon.2021.e05948 PMID: 33490692Jager, K.J.; Zoccali, C.; MacLeod, A.; Dekker, F.W. Confounding: What it is and how to deal with it. Kidney Int., 2008, 73(3), 256-260. doi: 10.1038/sj.ki.5002650 PMID: 17978811Schulz, K.F.; Altman, D.G.; Moher, D. CONSORT 2010 Statement: Updated guidelines for reporting parallel group randomised trials. BMJ, 2010, 340(1), c332. doi: 10.1136/bmj.c332 PMID: 20332509