{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T03:05:28Z","timestamp":1772507128749,"version":"3.50.1"},"reference-count":124,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T00:00:00Z","timestamp":1662508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fundo Europeu de Desenvolvimento Regional (FEDER)","award":["PTDC\/MEC-ONC\/29503\/2017"],"award-info":[{"award-number":["PTDC\/MEC-ONC\/29503\/2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Chemotherapy is a hallmark in high-grade serous carcinoma management; however, chemoresistance and side effects lead to therapeutic interruption. Combining repurposed drugs with chemotherapy has the potential to improve antineoplastic efficacy, since drugs can have independent mechanisms of action and suppress different pathways simultaneously. This study aimed to explore whether the combination of Paclitaxel with repurposed drugs led to a therapeutic benefit. Thus, we evaluated the cytotoxic effects of Paclitaxel alone and in combination with several repurposed drugs (Pitavastatin, Metformin, Ivermectin, Itraconazole and Alendronate) in two tumor chemoresistant (OVCAR8 and OVCAR8 PTX R P) and a non-tumoral (HOSE6.3) cell lines. Cellular viability was assessed using Presto Blue assay, and the synergistic interactions were evaluated using Chou\u2013Talalay, Bliss Independence and Highest Single Agent reference models. The combination of Paclitaxel with Pitavastatin or Ivermectin showed the highest cytotoxic effect and the strongest synergism among all combinations for both chemoresistant cell lines, resulting in a chemotherapeutic effect superior to both drugs alone. Almost all the repurposed drugs in combination with Paclitaxel presented a safe pharmacological profile in non-tumoral cells. Overall, we suggest that Pitavastatin and Ivermectin could act synergistically in combination with Paclitaxel, being promising two-drug combinations for high-grade serous carcinoma management.<\/jats:p>","DOI":"10.3390\/cancers14184357","type":"journal-article","created":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T20:52:03Z","timestamp":1662583923000},"page":"4357","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Pitavastatin and Ivermectin Enhance the Efficacy of Paclitaxel in Chemoresistant High-Grade Serous Carcinoma"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4733-5778","authenticated-orcid":false,"given":"Mariana","family":"Nunes","sequence":"first","affiliation":[{"name":"Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto\/Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal"},{"name":"Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1420-5042","authenticated-orcid":false,"given":"Diana","family":"Duarte","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), 4200-450 Porto, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), 4200-450 Porto, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4091-2226","authenticated-orcid":false,"given":"Sara","family":"Ricardo","sequence":"additional","affiliation":[{"name":"Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto\/Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal"},{"name":"Toxicology Research Unit (TOXRUN), University Institute of Health Sciences, Polytechnic and University Cooperative (CESPU), CRL, 4585-116 Gandra, Portugal"},{"name":"Department of Pathology, Faculty of Medicine, University of Porto (FMUP), 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Rickard, B.P., Conrad, C., Sorrin, A.J., Ruhi, M.K., Reader, J.C., Huang, S.A., Franco, W., Scarcelli, G., Polacheck, W.J., and Roque, D.M. (2021). Malignant Ascites in Ovarian Cancer: Cellular, Acellular, and Biophysical Determinants of Molecular Characteristics and Therapy Response. Cancers, 13.","DOI":"10.3390\/cancers13174318"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16061","DOI":"10.1038\/nrdp.2016.61","article-title":"Ovarian cancer","volume":"2","author":"Matulonis","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41416-020-0875-x","article-title":"The untapped potential of ascites in ovarian cancer research and treatment","volume":"123","author":"Ford","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1007\/s40265-014-0221-9","article-title":"First-line and maintenance therapy for ovarian cancer: Current status and future directions","volume":"74","author":"Bratos","year":"2014","journal-title":"Drugs"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1756-9966-31-14","article-title":"Therapeutic strategies in epithelial ovarian cancer","volume":"31","author":"Kim","year":"2012","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nrc1317","article-title":"Microtubules as a target for anticancer drugs","volume":"4","author":"Jordan","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"165","DOI":"10.2174\/157015906776359568","article-title":"Peripheral neuropathy induced by paclitaxel: Recent insights and future perspectives","volume":"4","author":"Scripture","year":"2006","journal-title":"Curr. Neuropharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"607780","DOI":"10.3389\/fphar.2020.607780","article-title":"Drug Repositioning for the Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy: A Mechanism- and Screening-Based Strategy","volume":"11","author":"Yamamoto","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Cree, I.A., and Charlton, P. (2017). Molecular chess? Hallmarks of anti-cancer drug resistance. BMC Cancer, 17.","DOI":"10.1186\/s12885-016-2999-1"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Di Nicolantonio, F., Mercer, S.J., Knight, L.A., Gabriel, F.G., Whitehouse, P.A., Sharma, S., Fernando, A., Glaysher, S., Di Palma, S., and Johnson, P. (2005). Cancer cell adaptation to chemotherapy. BMC Cancer, 5.","DOI":"10.1186\/1471-2407-5-78"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3389\/fphar.2020.00343","article-title":"The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents","volume":"11","author":"Zhou","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_12","first-page":"141","article-title":"Drug resistance and combating drug resistance in cancer","volume":"2","author":"Wang","year":"2019","journal-title":"Cancer Drug Resist."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/nrclinonc.2015.169","article-title":"Drug repurposing in oncology--patient and health systems opportunities","volume":"12","author":"Bertolini","year":"2015","journal-title":"Nat. Rev. Clin. Oncol"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1111\/bph.13895","article-title":"Drug repurposing screens and synergistic drug-combinations for infectious diseases","volume":"175","author":"Zheng","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Nunes, M., Henriques Abreu, M., Bartosch, C., and Ricardo, S. (2020). Recycling the Purpose of Old Drugs to Treat Ovarian Cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21207768"},{"key":"ref_16","first-page":"651","article-title":"New drugs are not enoughdrug repositioning in oncology: An update","volume":"56","author":"Armando","year":"2020","journal-title":"Int. J. Oncol"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1111\/jphp.13273","article-title":"Drug repositioning: A brief overview","volume":"72","author":"Jourdan","year":"2020","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"442","DOI":"10.3332\/ecancer.2014.485","article-title":"The Repurposing Drugs in Oncology (ReDO) Project","volume":"8","author":"Pantziarka","year":"2014","journal-title":"Ecancermedicalscience"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1186\/s12967-016-1031-5","article-title":"Repurposing of approved cardiovascular drugs","volume":"14","author":"Ishida","year":"2016","journal-title":"J. Transl. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1021\/ci500670q","article-title":"Systematic drug repositioning for a wide range of diseases with integrative analyses of phenotypic and molecular data","volume":"55","author":"Iwata","year":"2015","journal-title":"J. Chem Inf ModelJ. Chem. Inf. Model."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Correia, A., Silva, D., Correia, A., Vilanova, M., Gartner, F., and Vale, N. (2018). Study of New Therapeutic Strategies to Combat Breast Cancer Using Drug Combinations. Biomolecules, 8.","DOI":"10.3390\/biom8040175"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"38022","DOI":"10.18632\/oncotarget.16723","article-title":"Combination therapy in combating cancer","volume":"8","author":"Homayouni","year":"2017","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1158\/1535-7163.MCT-06-0084","article-title":"Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases","volume":"5","author":"Smalley","year":"2006","journal-title":"Mol. Cancer Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2232","DOI":"10.1111\/bph.13045","article-title":"Synergistic anti-tumour effects of tetrandrine and chloroquine combination therapy in human cancer: A potential antagonistic role for p21","volume":"172","author":"Mei","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e12380","DOI":"10.1111\/jpi.12380","article-title":"Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K\/AKT and NF-kappaB\/iNOS signaling pathways","volume":"62","author":"Gao","year":"2017","journal-title":"J. Pineal Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1016\/j.addr.2009.05.006","article-title":"Combination therapy: Opportunities and challenges for polymer-drug conjugates as anticancer nanomedicines","volume":"61","author":"Greco","year":"2009","journal-title":"Adv. Drug Deliv Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1016\/j.cell.2017.11.009","article-title":"Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy","volume":"171","author":"Palmer","year":"2017","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.pharmthera.2006.08.002","article-title":"Interactions between drugs and occupied receptors","volume":"113","author":"Tallarida","year":"2007","journal-title":"Pharmacol. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.drudis.2012.05.010","article-title":"Nanotechnology-based combinational drug delivery: An emerging approach for cancer therapy","volume":"17","author":"Parhi","year":"2012","journal-title":"Drug Discov. Today"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3223","DOI":"10.1021\/nl102184c","article-title":"Nanotechnology in drug delivery and tissue engineering: From discovery to applications","volume":"10","author":"Shi","year":"2010","journal-title":"Nano Lett."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Duarte, D., Cardoso, A., and Vale, N. (2021). Synergistic Growth Inhibition of HT-29 Colon and MCF-7 Breast Cancer Cells with Simultaneous and Sequential Combinations of Antineoplastics and CNS Drugs. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147408"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Duarte, D., and Vale, N. (2020). New Trends for Antimalarial Drugs: Synergism between Antineoplastics and Antimalarials on Breast Cancer Cells. Biomolecules, 10.","DOI":"10.3390\/biom10121623"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/s41416-019-0681-5","article-title":"Repurposing screen identifies mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment","volume":"122","author":"Rushworth","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_34","first-page":"6243","article-title":"Simvastatin potentiates doxorubicin activity against MCF-7 breast cancer cells","volume":"14","author":"Buranrat","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/s13058-019-1204-2","article-title":"Metformin overcomes resistance to cisplatin in triple-negative breast cancer (TNBC) cells by targeting RAD51","volume":"21","author":"Lee","year":"2019","journal-title":"Breast Cancer Res"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"752127","DOI":"10.3389\/fonc.2021.752127","article-title":"Generation of Two Paclitaxel-Resistant High-Grade Serous Carcinoma Cell Lines With Increased Expression of P-Glycoprotein","volume":"11","author":"Nunes","year":"2021","journal-title":"Front. Oncol"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1002\/ijc.2910450306","article-title":"Metallothionein gene expression and resistance to cisplatin in human ovarian cancer","volume":"45","author":"Schilder","year":"1990","journal-title":"Int. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1006\/excr.1995.1184","article-title":"Characterization of human ovarian surface epithelial cells immortalized by human papilloma viral oncogenes (HPV-E6E7 ORFs)","volume":"218","author":"Tsao","year":"1995","journal-title":"Exp. Cell Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5410","DOI":"10.1038\/s41598-017-05595-4","article-title":"Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer","volume":"7","author":"Abdullah","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_40","first-page":"7557","article-title":"Metformin in combination with cisplatin inhibits cell viability and induces apoptosis of human ovarian cancer cells by inactivating ERK 1\/2","volume":"14","author":"Dang","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_41","first-page":"243","article-title":"Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines","volume":"3","author":"Hashimoto","year":"2009","journal-title":"Drug Discov. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6552","DOI":"10.1038\/s41598-017-06510-7","article-title":"The anti-cancer effects of itraconazole in epithelial ovarian cancer","volume":"7","author":"Choi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1158\/0008-5472.540.65.2","article-title":"Alendronate inhibits intraperitoneal dissemination in in vivo ovarian cancer model","volume":"65","author":"Hashimoto","year":"2005","journal-title":"Cancer Res."},{"key":"ref_44","first-page":"97","article-title":"Synergistic combination of microtubule targeting anticancer fludelone with cytoprotective panaxytriol derived from panax ginseng against MX-1 cells in vitro: Experimental design and data analysis using the combination index method","volume":"6","author":"Zhang","year":"2016","journal-title":"Am. J. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","article-title":"Drug combination studies and their synergy quantification using the Chou-Talalay method","volume":"70","author":"Chou","year":"2010","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"158","DOI":"10.3389\/fphar.2017.00158","article-title":"An Introduction to Terminology and Methodology of Chemical Synergy-Perspectives from Across Disciplines","volume":"8","author":"Roell","year":"2017","journal-title":"Front. Pharmacol"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"W488","DOI":"10.1093\/nar\/gkaa216","article-title":"SynergyFinder 2.0: Visual analytics of multi-drug combination synergies","volume":"48","author":"Ianevski","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/s42256-019-0122-4","article-title":"Prediction of drug combination effects with a minimal set of exp.periments","volume":"1","author":"Ianevski","year":"2019","journal-title":"Nat. Mach. Intell"},{"key":"ref_49","first-page":"635","article-title":"The employment of combinations of drugs in the chemotherapy of neoplasia: A review","volume":"17","author":"Goldin","year":"1957","journal-title":"Cancer Res."},{"key":"ref_50","first-page":"331","article-title":"The search for synergy: A critical review from a response surface perspective","volume":"47","author":"Greco","year":"1995","journal-title":"Pharmacol. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies","volume":"58","author":"Chou","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"100110","DOI":"10.1016\/j.crphar.2022.100110","article-title":"Evaluation of synergism in drug combinations and reference models for future orientations in oncology","volume":"3","author":"Duarte","year":"2022","journal-title":"Curr Res. Pharmacol. Drug Discov."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.drudis.2021.09.012","article-title":"Combining repurposed drugs to treat colorectal cancer","volume":"27","author":"Duarte","year":"2021","journal-title":"Drug Discov. Today"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1200\/JCO.2012.42.0505","article-title":"OCEANS: A randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer","volume":"30","author":"Aghajanian","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"408","DOI":"10.2174\/1871520615666150113123039","article-title":"Combined anticancer therapies: An overview of the latest applications","volume":"15","author":"Piccolo","year":"2015","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"708943","DOI":"10.3389\/fonc.2021.708943","article-title":"Editorial: Novel Combination Therapies for the Treatment of Solid Cancers","volume":"11","author":"Ayoub","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"105401","DOI":"10.1016\/j.ejps.2020.105401","article-title":"Understanding Breast cancer: From conventional therapies to repurposed drugs","volume":"151","author":"Costa","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1136\/ijgc-00009577-200311001-00004","article-title":"Optimal therapy of advanced ovarian cancer: Carboplatin and paclitaxel versus cisplatin and paclitaxel (GOG158) and an update on GOG0182-ICON5","volume":"13","author":"Bookman","year":"2003","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1023\/A:1008365929809","article-title":"First line chemotherapy with carboplatin plus paclitaxel in advanced ovarian cancer--a new standard of care?","volume":"10","author":"Neijt","year":"1999","journal-title":"Ann. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3194","DOI":"10.1200\/JCO.2003.02.153","article-title":"Phase III trial of carbo.oplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynecologic Oncology Group study","volume":"21","author":"Ozols","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_61","first-page":"350","article-title":"Two drugs are better than one. A short history of combined therapy of ovarian cancer","volume":"19","author":"Bukowska","year":"2015","journal-title":"Contemp. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"133s","DOI":"10.1200\/JCO.2003.01.066","article-title":"Current status of taxane and platinum-based chemotherapy in ovarian cancer","volume":"21","author":"McGuire","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ctrv.2006.09.006","article-title":"Molecular mechanisms of resistance and toxicity associated with platinating agents","volume":"33","author":"Rabik","year":"2007","journal-title":"Cancer Treat. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Dermitzakis, E.V., Kimiskidis, V.K., Lazaridis, G., Alexopoulou, Z., Timotheadou, E., Papanikolaou, A., Romanidou, O., Georgiadis, G., Kalogeras, K.T., and Tsiptsios, I. (2016). The impact of paclitaxel and carboplatin chemotherapy on the autonomous nervous system of patients with ovarian cancer. BMC Neurol., 16.","DOI":"10.1186\/s12883-016-0710-4"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S1359-6349(15)70005-4","article-title":"Limitations to the use of carboplatin-based therapy in advanced ovarian cancer","volume":"12","author":"Fotopoulou","year":"2014","journal-title":"Eur. J. Cancer Suppl."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"6804","DOI":"10.1021\/acsami.6b14244","article-title":"Positively Charged Combinatory Drug Delivery Systems against Multi-Drug-Resistant Breast Cancer: Beyond the Drug Combination","volume":"9","author":"Yan","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.drudis.2006.11.008","article-title":"Multi-target therapeutics: When the whole is greater than the sum of the parts","volume":"12","author":"Zimmermann","year":"2007","journal-title":"Drug Discov. Today"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4370","DOI":"10.1158\/0008-5472.CAN-17-3993","article-title":"Licofelone Enhances the Efficacy of Paclitaxel in Ovarian Cancer by Reversing Drug Resistance and Tumor Stem-like Properties","volume":"78","author":"Hirst","year":"2018","journal-title":"Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4535","DOI":"10.21873\/anticanres.12757","article-title":"A Small-molecule Kinase Inhibitor, CEP-1347, Inhibits Survivin Expression and Sensitizes Ovarian Cancer Stem Cells to Paclitaxel","volume":"38","author":"Togashi","year":"2018","journal-title":"Anticancer Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"6699","DOI":"10.21873\/anticanres.13038","article-title":"AS602801, an Anticancer Stem Cell Candidate Drug, Reduces Survivin Expression and Sensitizes A2780 Ovarian Cancer Stem Cells to Carboplatin and Paclitaxel","volume":"38","author":"Yamamoto","year":"2018","journal-title":"Anticancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Branco, H., Oliveira, J., Antunes, C., Santos, L.L., Vasconcelos, M.H., and Xavier, C.P.R. (2022). Pirfenidone Sensitizes NCI-H460 Non-Small Cell Lung Cancer Cells to Paclitaxel and to a Combination of Paclitaxel with Carboplatin. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073631"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Martirosyan, A., Clendening, J.W., Goard, C.A., and Penn, L.Z. (2010). Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: Potential therapeutic relevance. BMC Cancer, 10.","DOI":"10.1186\/1471-2407-10-103"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.ygyno.2013.02.003","article-title":"Preclinical evaluation of statins as a treatment for ovarian cancer","volume":"129","author":"Robinson","year":"2013","journal-title":"Gynecol. Oncol."},{"key":"ref_74","first-page":"915","article-title":"Erratum: Atorvastatin exhibits anti-tumorigenic and anti-m.metastatic effects in ovarian cancer in vitro","volume":"8","author":"Jones","year":"2018","journal-title":"Am. J. Cancer Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"946","DOI":"10.18632\/oncotarget.5834","article-title":"The HMG-CoA reductase inhibitor, simvastatin, exhibits anti-metastatic and anti-tumorigenic effects in ovarian cancer","volume":"7","author":"Stine","year":"2016","journal-title":"Oncotarget"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"479.e1","DOI":"10.1016\/j.ajog.2014.10.026","article-title":"Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models","volume":"212","author":"Lengyel","year":"2015","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_77","first-page":"2404","article-title":"Metformin improves the sensitivity of ovarian cancer cells to chemotherapeutic agents","volume":"18","author":"Yang","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Du, J., Shi, H.R., Ren, F., Wang, J.L., Wu, Q.H., Li, X., and Zhang, R.T. (2017). Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cells. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3840-1"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1593\/neo.11148","article-title":"Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo","volume":"13","author":"Rattan","year":"2011","journal-title":"Neoplasia"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2346","DOI":"10.3892\/mmr.2014.2490","article-title":"Metformin combined with p38 MAPK inhibitor improves cisplatin sensitivity in cisplatinresistant ovarian cancer","volume":"10","author":"Xie","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"E7301","DOI":"10.1073\/pnas.1705441114","article-title":"In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer","volume":"114","author":"Kodama","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.amjms.2019.11.001","article-title":"Ivermectin Augments the In Vitro and In Vivo Efficacy of Cisplatin in Epithelial Ovarian Cancer by Suppressing Akt\/mTOR Signaling","volume":"359","author":"Zhang","year":"2020","journal-title":"Am. J. Med. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1186\/s13046-019-1251-7","article-title":"Ivermectin reverses the drug resistance in cancer cells through EGFR\/ERK\/Akt\/NF-kappaB pathway","volume":"38","author":"Jiang","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"521","DOI":"10.3332\/ecancer.2015.521","article-title":"Repurposing Drugs in Oncology (ReDO)-itraconazole as an anti-cancer agent","volume":"9","author":"Pantziarka","year":"2015","journal-title":"Ecancermedicalscience"},{"key":"ref_85","first-page":"2481","article-title":"Impact of combination chemotherapy with itraconazole on survival of patients with refractory ovarian cancer","volume":"34","author":"Tsubamoto","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_86","first-page":"4191","article-title":"Combination Chemotherapy with Itraconazole for Treating Metastatic Pancreatic Cancer in the Second-line or Additional Setting","volume":"35","author":"Tsubamoto","year":"2015","journal-title":"Anticancer Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1248\/bpb.22.1355","article-title":"Cellular pharmacokinetic aspects of reversal effect of itraconazole on P-glycoprotein-mediated resistance of anticancer drugs","volume":"22","author":"Takara","year":"1999","journal-title":"Biol. Pharm. Bull."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"173892","DOI":"10.1016\/j.ejphar.2021.173892","article-title":"Itraconazole synergistically increases therapeutic effect of paclitaxel and (99m)Tc-MIBI accumulation, as a probe of P-gp activity, in HT-29 tumor-bearing nude mice","volume":"895","author":"Ghadi","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1248\/bpb.24.1032","article-title":"Reversal effects of antifungal drugs on multidrug resistance in MDR1-overexpressing HeLa cells","volume":"24","author":"Iida","year":"2001","journal-title":"Biol. Pharm. Bull."},{"key":"ref_90","first-page":"5295","article-title":"Zoledronic acid as an antimetastatic agent for different human tumor cell lines","volume":"33","author":"Garcia","year":"2013","journal-title":"Anticancer Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1038\/sj.bjc.6605604","article-title":"The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: Exploratory evidence for direct anti-tumour activity in breast cancer","volume":"102","author":"Coleman","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1007\/s12094-011-0634-9","article-title":"Direct antitumour activity of zoledronic acid: Preclinical and clinical data","volume":"13","author":"Merajver","year":"2011","journal-title":"Clin. Transl. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"106","DOI":"10.2174\/1570163811310020003","article-title":"Drugs and their interactions","volume":"10","author":"Cokol","year":"2013","journal-title":"Curr. Drug Discov. Technol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1677\/ERC-10-0009","article-title":"Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity and of Ras farnesylation mediate antitumor effects of anandamide in human breast cancer cells","volume":"17","author":"Laezza","year":"2010","journal-title":"Endocrine-Related Cancer"},{"key":"ref_95","first-page":"328","article-title":"HMG-CoA Reductase Inhibitors (Statins) and their Drug Interactions Involving CYP Enzymes, P-glycoprotein and OATP Transporters-An Overview","volume":"22","author":"Balasubramanian","year":"2021","journal-title":"Curr. Drug Metab."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nature08097","article-title":"Enhancing CD8 T-cell memory by modulating fatty acid metabolism","volume":"460","author":"Pearce","year":"2009","journal-title":"Nature"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"330","DOI":"10.18632\/aging.100556","article-title":"Metformin, aging and cancer","volume":"5","author":"Moiseeva","year":"2013","journal-title":"Aging"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1158\/1940-6207.CAPR-08-0081","article-title":"The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activa.ated protein kinase","volume":"1","author":"Zakikhani","year":"2008","journal-title":"Cancer Prev. Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.semcdb.2019.05.010","article-title":"The multifaceted effects of metformin on tumor microenvironment","volume":"98","author":"Kurelac","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1097\/00001813-199609000-00005","article-title":"The abamectin derivative ivermectin is a potent P-glycoprotein inhibitor","volume":"7","author":"Didier","year":"1996","journal-title":"Anticancer Drugs"},{"key":"ref_101","first-page":"317","article-title":"The multitargeted drug ivermectin: From an antiparasitic agent to a repositioned cancer drug","volume":"8","author":"Juarez","year":"2018","journal-title":"Am. J. Cancer Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.15252\/emmm.201404084","article-title":"The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer","volume":"6","author":"Melotti","year":"2014","journal-title":"EMBO Mol. Med."},{"key":"ref_103","first-page":"3397","article-title":"Ivermectin as an inhibitor of cancer stemlike cells","volume":"17","author":"Juarez","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"BSR20192489","DOI":"10.1042\/BSR20192489","article-title":"Ivermectin induces autophagy-mediated cell death through the AKT\/mTOR signaling pathway in glioma cells","volume":"39","author":"Liu","year":"2019","journal-title":"Biosci. Rep."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Seth, C., Mas, C., Conod, A., Mueller, J., Siems, K., Kuciak, M., Borges, I., and Ruiz i Altaba, A. (2016). Long-Lasting WNT-TCF Response Blocking and Epigenetic Modifying Activities of Withanolide F in Human Cancer Cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168170"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.ccr.2010.02.027","article-title":"Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth","volume":"17","author":"Kim","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.4161\/auto.28912","article-title":"Itraconazole suppresses the growth of glioblastoma through induction of autophagy: Involvement of abnormal cholesterol trafficking","volume":"10","author":"Liu","year":"2014","journal-title":"Autophagy"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"28510","DOI":"10.18632\/oncotarget.15324","article-title":"Itraconazole exerts its anti-melanoma effect by suppressing Hedgehog, Wnt, and PI3K\/mTOR signaling pathways","volume":"8","author":"Liang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"515","DOI":"10.21873\/anticanres.11343","article-title":"Itraconazole Inhibits AKT\/mTOR Signaling and Proliferation in Endometrial Cancer Cells","volume":"37","author":"Tsubamoto","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_110","first-page":"3521","article-title":"Itraconazole Modulates Hedgehog, WNT\/beta-catenin, as well as Akt Signalling, and Inhibits Proliferation of Cervical Cancer Cells","volume":"37","author":"Ueda","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/BF01701730","article-title":"Itraconazole and multidrug resistance: Possible effects on remission rate and disease-free survival in acute leukemia","volume":"67","author":"Vreugdenhil","year":"1993","journal-title":"Ann. Hematol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1111\/j.1349-7006.1999.tb00723.x","article-title":"Interaction of docetaxel (\u201cTaxotere\u201d) with human P-glycoprotein","volume":"90","author":"Shirakawa","year":"1999","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/nrclinonc.2013.169","article-title":"Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates","volume":"10","author":"Gronich","year":"2013","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.2174\/092986707781389600","article-title":"Zoledronic acid\u2014A multiplicity of anti-cancer action","volume":"14","author":"Yuasa","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1097\/01.cad.0000176500.56057.66","article-title":"Pilot studies of the effect of zoledronic acid (Zometa) on tumor-derived cells ex vivo in the ATP-based tumor chemosensitivity assay","volume":"16","author":"Knight","year":"2005","journal-title":"Anticancer Drugs"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"576559","DOI":"10.3389\/fonc.2020.576559","article-title":"P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers","volume":"10","author":"Seelig","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/1475-2867-5-30","article-title":"ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal","volume":"5","author":"Choi","year":"2005","journal-title":"Cancer Cell Int."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"793","DOI":"10.2174\/138161282005140214165212","article-title":"ABC transporters in multidrug resistance and pharmacokinetics, and strategies for drug development","volume":"20","author":"Choi","year":"2014","journal-title":"Curr. Pharm Des."},{"key":"ref_119","first-page":"177","article-title":"Inhibition of P-glycoprotein expression and function by anti-diabetic drugs gliclazide, metformin, and pioglitazone in vitro and in situ","volume":"11","author":"Abbasi","year":"2016","journal-title":"Res. Pharm Sci."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.18632\/oncotarget.23187","article-title":"Metformin synergistically suppress tumor growth with doxorubicin and reverse drug resistance by inhibiting the expression and function of P-glycoprotein in MCF7\/ADR cells and xenograft models","volume":"9","author":"Li","year":"2018","journal-title":"Oncotarget"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.cbi.2005.11.002","article-title":"Interaction of ivermectin with multidrug resistance proteins (MRP1, 2 and 3)","volume":"159","author":"Lespine","year":"2006","journal-title":"Chem. Biol. Interact."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1177\/0091270010365885","article-title":"Itraconazole, a P-glycoprotein and CYP3A4 inhibitor, markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren","volume":"51","author":"Tapaninen","year":"2011","journal-title":"J. Clin. Pharmacol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1128\/AAC.42.7.1738","article-title":"P-glycoprotein-mediated transport of itraconazole across the blood-brain barrier","volume":"42","author":"Miyama","year":"1998","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1111\/bcp.12377","article-title":"Pitavastatin is a more sensitive and selective organic anion-transporting polypeptide 1B clinical probe than rosuvastatin","volume":"78","author":"Prueksaritanont","year":"2014","journal-title":"Br. J. Clin. Pharmacol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/18\/4357\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:25:15Z","timestamp":1760142315000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/18\/4357"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,7]]},"references-count":124,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["cancers14184357"],"URL":"https:\/\/doi.org\/10.3390\/cancers14184357","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,7]]}}}