{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T21:46:16Z","timestamp":1780091176000,"version":"3.54.0"},"reference-count":94,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,16]],"date-time":"2020-10-16T00:00:00Z","timestamp":1602806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["1160139"],"award-info":[{"award-number":["1160139"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["1130250"],"award-info":[{"award-number":["1130250"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["1170925"],"award-info":[{"award-number":["1170925"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Comisi\u00f3n Nacional de Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica - Fondo de Financiamiento de Centros de Investigaci\u00f3n en \u00c1reas Prioritarias","award":["15130011"],"award-info":[{"award-number":["15130011"]}]},{"name":"Comisi\u00f3n Nacional de Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica - Beca Doctorado Nacional","award":["21150360"],"award-info":[{"award-number":["21150360"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Epithelial ovarian cancer (EOC) is a lethal gynaecological neoplasm characterized by rapid growth and angiogenesis. Nerve growth factor (NGF) and its high affinity receptor tropomyosin receptor kinase A (TRKA) contribute to EOC progression by increasing the expression of c-MYC, survivin and vascular endothelial growth factor (VEGF) along with a decrease in microRNAs (miR) 23b and 145. We previously reported that metformin prevents NGF-induced proliferation and angiogenic potential of EOC cells. In this study, we sought to obtain a better understanding of the mechanism(s) by which metformin blocks these NGF-induced effects in EOC cells. Human ovarian surface epithelial (HOSE) and EOC (A2780\/SKOV3) cells were stimulated with NGF and\/or metformin to assess the expression of c-MYC, \u03b2-catenin, survivin and VEGF and the abundance of the tumor suppressor miRs 23b and 145. Metformin decreased the NGF-induced transcriptional activity of MYC and \u03b2-catenin\/T-cell factor\/lymphoid enhancer-binding factor (TCF-Lef), as well as the expression of c-MYC, survivin and VEGF in EOC cells, while it increased miR-23b and miR-145 levels. The preliminary analysis of ovarian biopsies from women users or non-users of metformin was consistent with these in vitro results. Our observations shed light on the mechanisms by which metformin may suppress tumour growth in EOC and suggest that metformin should be considered as a possible complementary therapy in EOC treatment.<\/jats:p>","DOI":"10.3390\/ph13100315","type":"journal-article","created":{"date-parts":[[2020,10,15]],"date-time":"2020-10-15T21:42:21Z","timestamp":1602798141000},"page":"315","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Metformin Reduces NGF-Induced Tumour Promoter Effects in Epithelial Ovarian Cancer Cells"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7234-3916","authenticated-orcid":false,"given":"Maritza P.","family":"Garrido","sequence":"first","affiliation":[{"name":"Laboratorio de Endocrinolog\u00eda y Biolog\u00eda de la Reproducci\u00f3n, Hospital Cl\u00ednico Universidad de Chile, Santiago 8380456, Chile"},{"name":"Departamento de Obstetricia y Ginecolog\u00eda, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato","family":"Salvatierra","sequence":"additional","affiliation":[{"name":"Laboratorio de Endocrinolog\u00eda y Biolog\u00eda de la Reproducci\u00f3n, Hospital Cl\u00ednico Universidad de Chile, Santiago 8380456, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8833-7382","authenticated-orcid":false,"given":"Manuel","family":"Valenzuela-Valderrama","sequence":"additional","affiliation":[{"name":"Laboratorio de Microbiolog\u00eda Celular, Instituto de Investigaci\u00f3n e Innovaci\u00f3n en Salud, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago 8320000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Vallejos","sequence":"additional","affiliation":[{"name":"Laboratorio de Endocrinolog\u00eda y Biolog\u00eda de la Reproducci\u00f3n, Hospital Cl\u00ednico Universidad de Chile, Santiago 8380456, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Bruneau","sequence":"additional","affiliation":[{"name":"Laboratorio de Endocrinolog\u00eda y Biolog\u00eda de la Reproducci\u00f3n, Hospital Cl\u00ednico Universidad de Chile, Santiago 8380456, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Laboratorio de Endocrinolog\u00eda y Biolog\u00eda de la Reproducci\u00f3n, Hospital Cl\u00ednico Universidad de Chile, Santiago 8380456, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarita","family":"Vega","sequence":"additional","affiliation":[{"name":"Laboratorio de Endocrinolog\u00eda y Biolog\u00eda de la Reproducci\u00f3n, Hospital Cl\u00ednico Universidad de Chile, Santiago 8380456, Chile"},{"name":"Departamento de Obstetricia y Ginecolog\u00eda, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Selman","sequence":"additional","affiliation":[{"name":"Departamento de Obstetricia y Ginecolog\u00eda, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile"},{"name":"Instituto Nacional del C\u00e1ncer, Santiago 8380455, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8755-1590","authenticated-orcid":false,"given":"Andrew F. G.","family":"Quest","sequence":"additional","affiliation":[{"name":"Laboratorio de Comunicaciones Celulares, Centro de estudios en Ejercicio, Metabolismo y C\u00e1ncer (CEMC), Programa de Biolog\u00eda Celular y Molecular, Instituto de Ciencias Biom\u00e9dicas (ICBM), Facultad De Medicina, Universidad de Chile, Santiago 8380453, Chile"},{"name":"Advanced Center for Chronic Diseases (ACCDiS), Santiago 8380000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Romero","sequence":"additional","affiliation":[{"name":"Laboratorio de Endocrinolog\u00eda y Biolog\u00eda de la Reproducci\u00f3n, Hospital Cl\u00ednico Universidad de Chile, Santiago 8380456, Chile"},{"name":"Departamento de Obstetricia y Ginecolog\u00eda, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.20892\/j.issn.2095-3941.2016.0084","article-title":"Epidemiology of ovarian cancer: A review","volume":"14","author":"Reid","year":"2017","journal-title":"Cancer Biol. Med."},{"key":"ref_2","unstructured":"American Cancer Society (2020, September 21). Survival Rates for Ovarian Cancer, by Stage. Available online: https:\/\/www.cancer.org\/cancer\/ovarian-cancer\/detection-diagnosis-staging\/survival-rates.html."},{"key":"ref_3","unstructured":"Cancer Research UK (2020, September 21). Ovarian Cancer. Available online: https:\/\/www.cancerresearchuk.org\/about-cancer\/ovarian-cancer\/survival."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ygyno.2010.12.341","article-title":"Tyrosine kinase a receptor (trka): A potential marker in epithelial ovarian cancer","volume":"121","author":"Tapia","year":"2011","journal-title":"Gynecol. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1071\/RD12112","article-title":"Targeting angiogenesis in the pathological ovary","volume":"25","author":"Duncan","year":"2013","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_6","first-page":"937","article-title":"Diagnosis and management of ovarian cancer","volume":"93","author":"Doubeni","year":"2016","journal-title":"Am. Fam. Physician"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1055\/s-0032-1304617","article-title":"Nerve growth factor stimulates cellular proliferation of human epithelial ovarian cancer","volume":"44","author":"Urzua","year":"2012","journal-title":"Horm. Metab. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.ygyno.2006.07.007","article-title":"Nerve growth factor and its high-affinity receptor trka participate in the control of vascular endothelial growth factor expression in epithelial ovarian cancer","volume":"104","author":"Campos","year":"2007","journal-title":"Gynecol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"913","DOI":"10.3389\/fonc.2019.00913","article-title":"Angiogenesis in gynecological cancers: Role of neurotrophins","volume":"9","author":"Garrido","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Garrido, M.P., Hurtado, I., Valenzuela-Valderrama, M., Salvatierra, R., Hernandez, A., Vega, M., Selman, A., Quest, A.F.G., and Romero, C. (2019). Ngf-enhanced vasculogenic properties of epithelial ovarian cancer cells is reduced by inhibition of the cox-2\/pge2 signaling axis. Cancers, 11.","DOI":"10.3390\/cancers11121970"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1749-8104-8-7","article-title":"Akt activation by n-cadherin regulates beta-catenin signaling and neuronal differentiation during cortical development","volume":"8","author":"Zhang","year":"2013","journal-title":"Neural. Dev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1128\/IAI.01025-10","article-title":"Epithelial phosphatidylinositol-3-kinase signaling is required for beta-catenin activation and host defense against citrobacter rodentium infection","volume":"79","author":"Brown","year":"2011","journal-title":"Infect. Immun."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Krejci, P., Aklian, A., Kaucka, M., Sevcikova, E., Prochazkova, J., Masek, J.K., Mikolka, P., Pospisilova, T., Spoustova, T., and Weis, M. (2012). Receptor tyrosine kinases activate canonical wnt\/beta-catenin signaling via map kinase\/lrp6 pathway and direct beta-catenin phosphorylation. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035826"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.bbrc.2010.03.165","article-title":"Regulation of survivin by pi3k\/akt\/p70s6k1 pathway","volume":"395","author":"Zhao","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1038\/onc.2013.122","article-title":"Erk and akt signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer","volume":"33","author":"Ye","year":"2014","journal-title":"Oncogene"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.gene.2018.08.047","article-title":"Prognostic significance of beta-catenin expression in patients with ovarian cancer: A meta-analysis","volume":"678","author":"Long","year":"2018","journal-title":"Gene"},{"key":"ref_17","first-page":"121","article-title":"Survivin expression in ovarian cancer","volume":"29","author":"Liguang","year":"2007","journal-title":"Exp. Oncol."},{"key":"ref_18","first-page":"PI25","article-title":"Survivin-an anti-apoptosis protein: Its biological roles and implications for cancer and beyond","volume":"9","author":"Chiou","year":"2003","journal-title":"Med. Sci. Monit."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1158\/1535-7163.MCT-05-0375","article-title":"Survivin, a cancer target with an emerging role in normal adult tissues","volume":"5","author":"Fukuda","year":"2006","journal-title":"Mol. Cancer Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"314","DOI":"10.7150\/jca.13332","article-title":"Survivin and tumorigenesis: Molecular mechanisms and therapeutic strategies","volume":"7","author":"Chen","year":"2016","journal-title":"J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11018","DOI":"10.1158\/0008-5472.CAN-05-0491","article-title":"Survivin expression is regulated by coexpression of human epidermal growth factor receptor 2 and epidermal growth factor receptor via phosphatidylinositol 3-kinase\/akt signaling pathway in breast cancer cells","volume":"65","author":"Asanuma","year":"2005","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/nrc968","article-title":"Validating survivin as a cancer therapeutic target","volume":"3","author":"Altieri","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1186\/s12943-015-0467-1","article-title":"The twisted survivin connection to angiogenesis","volume":"14","author":"Sanhueza","year":"2015","journal-title":"Mol. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1097\/01.MP.0000073868.31297.B0","article-title":"Survivin expression in ovarian carcinoma: Correlation with apoptotic markers and prognosis","volume":"16","author":"Cohen","year":"2003","journal-title":"Mod. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1186\/1476-4598-13-209","article-title":"Survivin expression promotes vegf-induced tumor angiogenesis via pi3k\/akt enhanced beta-catenin\/tcf-lef dependent transcription","volume":"13","author":"Fernandez","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1126\/science.1962194","article-title":"A homolog of the armadillo protein in drosophila (plakoglobin) associated with e-cadherin","volume":"254","author":"McCrea","year":"1991","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/382638a0","article-title":"Functional interaction of beta-catenin with the transcription factor lef-1","volume":"382","author":"Behrens","year":"1996","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/385829a0","article-title":"Pangolin encodes a lef-1 homologue that acts downstream of armadillo to transduce the wingless signal in drosophila","volume":"385","author":"Brunner","year":"1997","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1101\/gad.1686208","article-title":"Deciphering the function of canonical wnt signals in development and disease: Conditional loss- and gain-of-function mutations of beta-catenin in mice","volume":"22","author":"Grigoryan","year":"2008","journal-title":"Genes Dev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1172\/JCI36183","article-title":"Biomarkers for epithelial-mesenchymal transitions","volume":"119","author":"Zeisberg","year":"2009","journal-title":"J. Clin. Invest."},{"key":"ref_31","first-page":"1906","article-title":"Twist is up-regulated in response to wnt1 and inhibits mouse mammary cell differentiation","volume":"63","author":"Howe","year":"2003","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.21037\/tcr.2019.08.25","article-title":"Wnt\/b-catenin signaling pathway is involved in induction of apoptosis by oridonin in colon cancer colo205 cells","volume":"8","author":"Bu","year":"2019","journal-title":"Transl. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1186\/s13046-019-1342-5","article-title":"The small molecule wnt\/beta-catenin inhibitor cwp232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway","volume":"38","author":"Pak","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0092-8674(04)00045-5","article-title":"Micrornas: Genomics, biogenesis, mechanism, and function","volume":"116","author":"Bartel","year":"2004","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Retamales-Ortega, R., Orostica, L., Vera, C., Cuevas, P., Hernandez, A., Hurtado, I., Vega, M., and Romero, C. (2017). Role of nerve growth factor (ngf) and mirnas in epithelial ovarian cancer. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030507"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.ajog.2008.09.010","article-title":"Use of metformin in polycystic ovary syndrome","volume":"199","author":"Mathur","year":"2008","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"157","DOI":"10.3132\/dvdr.2008.027","article-title":"Metformin therapy and clinical uses","volume":"5","author":"Scarpello","year":"2008","journal-title":"Diabetes Vasc. Dis. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"212282","DOI":"10.7573\/dic.212282","article-title":"A review of current treatment strategies for gestational diabetes mellitus","volume":"4","author":"Kelley","year":"2015","journal-title":"Drugs Context"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.ygyno.2011.06.038","article-title":"Use of metformin and the risk of ovarian cancer: A case-control analysis","volume":"123","author":"Bodmer","year":"2011","journal-title":"Gynecol. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1136\/ijgc-2018-000060","article-title":"Association of metformin use with ovarian cancer incidence and prognosis: A systematic review and meta-analysis","volume":"29","author":"Shi","year":"2019","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1038\/onc.2016.391","article-title":"Metformin alters DNA methylation genome-wide via the h19\/sahh axis","volume":"36","author":"Zhong","year":"2016","journal-title":"Oncogene"},{"key":"ref_42","first-page":"1899","article-title":"Metformin inhibits ovarian cancer via decreasing h3k27 trimethylation","volume":"52","author":"Tang","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.freeradbiomed.2014.06.010","article-title":"Metformin induces microrna-34a to downregulate the sirt1\/pgc-1alpha\/nrf2 pathway, leading to increased susceptibility of wild-type p53 cancer cells to oxidative stress and therapeutic agents","volume":"74","author":"Do","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"29","DOI":"10.12659\/MSM.898710","article-title":"Metformin induces growth inhibition and cell cycle arrest by upregulating microrna34a in renal cancer cells","volume":"23","author":"Xie","year":"2017","journal-title":"Med. Sci. Monit."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1158\/1940-6207.CAPR-11-0299","article-title":"Metformin inhibits cell proliferation, migration and invasion by attenuating csc function mediated by deregulating mirnas in pancreatic cancer cells","volume":"5","author":"Bao","year":"2012","journal-title":"Cancer Prev. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1758835918770984","DOI":"10.1177\/1758835918770984","article-title":"Metformin prevents nerve growth factor-dependent proliferative and proangiogenic effects in epithelial ovarian cancer cells and endothelial cells","volume":"10","author":"Garrido","year":"2018","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11221","DOI":"10.1074\/jbc.M611871200","article-title":"Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity","volume":"282","author":"Fang","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Yan, X., Lyu, T., Jia, N., Yu, Y., Hua, K., and Feng, W. (2013). Huaier aqueous extract inhibits ovarian cancer cell motility via the akt\/gsk3beta\/beta-catenin pathway. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063731"},{"key":"ref_49","unstructured":"The European Collection of Authenticated Cell Cultures (ECACC) (2020, September 21). Cell Line Profile: Ovarian Cancer Cell Line a2780. Available online: https:\/\/www.phe-culturecollections.org.uk\/media\/113526\/a2780-cell-line-profile.pdf."},{"key":"ref_50","unstructured":"American Type Culture Collection (ATCC) (2020, September 21). Sk-ov-3 [skov-3; skov3] (atcc\u00ae htb-77\u2122). Available online: https:\/\/www.atcc.org\/Products\/All\/HTB-77.aspx#documentation."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5515","DOI":"10.1038\/s41598-019-41941-4","article-title":"Ovarian cancer cell lines derived from non-serous carcinomas migrate and invade more aggressively than those derived from high-grade serous carcinomas","volume":"9","author":"Dawson","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S0015-0282(00)00670-1","article-title":"Role of vascular endothelial growth factor in ovarian physiology and pathology","volume":"74","author":"Geva","year":"2000","journal-title":"Fertil. Steril."},{"key":"ref_53","first-page":"2253","article-title":"Vascular endothelial growth factor splice variants and their prognostic value in breast and ovarian cancer","volume":"8","author":"Stimpfl","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/nature07228","article-title":"Widespread changes in protein synthesis induced by micrornas","volume":"455","author":"Selbach","year":"2008","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/nature07242","article-title":"The impact of micrornas on protein output","volume":"455","author":"Baek","year":"2008","journal-title":"Nature"},{"key":"ref_56","unstructured":"World Ovarian Cancer Coalition (2020, September 28). The World Ovarian Cancer Coalition Atlas. Available online: https:\/\/worldovariancancercoalition.org\/wp-content\/uploads\/2018\/10\/THE-WORLD-OVARIAN-CANCER-COALITION-ATLAS-2018.pdf."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.3892\/or.2013.2718","article-title":"Metformin suppresses hepatocellular carcinoma cell growth through induction of cell cycle g1\/g0 phase arrest and p21cip and p27kip expression and downregulation of cyclin d1 in vitro and in vivo","volume":"30","author":"Cai","year":"2013","journal-title":"Oncol. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"7018","DOI":"10.1002\/cam4.2560","article-title":"Ovarian cancer: Current status and strategies for improving therapeutic outcomes","volume":"8","author":"Chandra","year":"2019","journal-title":"Cancer Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1111\/bcp.12525","article-title":"The pharmacokinetics of metformin and concentrations of haemoglobin a1c and lactate in indigenous and non-indigenous australians with type 2 diabetes mellitus","volume":"79","author":"Duong","year":"2014","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_60","unstructured":"FDA (2020, July 14). Glumetza, 500 mg (Metformin Hydrochloride Extended Release Tablets), Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2009\/021748s005lbl.pdf."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3109\/00498259409043220","article-title":"Accumulation of metformin by tissues of the normal and diabetic mouse","volume":"24","author":"Wilcock","year":"1994","journal-title":"Xenobiotica"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cmet.2016.09.005","article-title":"Metformin targets central carbon metabolism and reveals mitochondrial requirements in human cancers","volume":"24","author":"Liu","year":"2016","journal-title":"Cell Metab."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1006\/exnr.1994.1093","article-title":"Pharmacokinetics of nerve growth factor (ngf) following different routes of administration to adult rats","volume":"127","author":"Tria","year":"1994","journal-title":"Exp. Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1002\/dmrr.2649","article-title":"Metformin reduces ovarian cancer risk in taiwanese women with type 2 diabetes mellitus","volume":"31","author":"Tseng","year":"2015","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Shin, H.Y., Yang, W., Lee, E.J., Han, G.H., Cho, H., Chay, D.B., and Kim, J.H. (2018). Establishment of five immortalized human ovarian surface epithelial cell lines via sv40 t antigen or hpv e6\/e7 expression. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0205297"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/S0002-9378(11)91579-8","article-title":"Simian virus 40-transformed human ovarian surface epithelial cells escape normal growth controls but retain morphogenetic responses to extracellular matrix","volume":"167","author":"Kruk","year":"1992","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Beaufort, C.M., Helmijr, J.C., Piskorz, A.M., Hoogstraat, M., Ruigrok-Ritstier, K., Besselink, N., Murtaza, M., van, I.W.F., Heine, A.A., and Smid, M. (2014). Ovarian cancer cell line panel (occp): Clinical importance of in vitro morphological subtypes. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0103988"},{"key":"ref_68","first-page":"3086","article-title":"Metformin inhibits ovarian cancer growth and migration in vitro and in vivo by enhancing cisplatin cytotoxicity","volume":"10","author":"Zheng","year":"2018","journal-title":"Am. J. Transl. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4080","DOI":"10.1158\/1538-7445.AM2011-4080","article-title":"Abstract 4080: Metformin and rapamycin inhibit proliferation and alter glucose metabolism in endometrial and ovarian cancer cell lines","volume":"71","author":"Zhou","year":"2011","journal-title":"Cancer Res."},{"key":"ref_70","first-page":"6739","article-title":"Mir-145: A potential biomarker of cancer migration and invasion","volume":"11","author":"Xu","year":"2019","journal-title":"Am. J. Transl. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.trsl.2016.03.016","article-title":"New models of hematogenous ovarian cancer metastasis demonstrate preferential spread to the ovary and a requirement for the ovary for abdominal dissemination","volume":"175","author":"Coffman","year":"2016","journal-title":"Transl. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1074\/jbc.M110.211714","article-title":"Pro-nerve growth factor induces autocrine stimulation of breast cancer cell invasion through tropomyosin-related kinase a (trka) and sortilin protein","volume":"287","author":"Demont","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1038\/jid.2008.21","article-title":"Neurotrophins and their receptors stimulate melanoma cell proliferation and migration","volume":"128","author":"Truzzi","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"81026","DOI":"10.18632\/oncotarget.13186","article-title":"Nerve growth factor modulates the tumor cells migration in ovarian cancer through the wnt\/beta-catenin pathway","volume":"7","author":"Li","year":"2016","journal-title":"Oncotarget"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1038\/ncomms3126","article-title":"Evaluating cell lines as tumour models by comparison of genomic profiles","volume":"4","author":"Domcke","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_76","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_77","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1111\/bcp.12251","article-title":"Micrornas and their relevance to abc transporters","volume":"77","author":"Haenisch","year":"2014","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1124\/mol.112.081844","article-title":"Microrna-145 post-transcriptionally regulates the expression and function of p-glycoprotein in intestinal epithelial cells","volume":"83","author":"Ikemura","year":"2013","journal-title":"Mol. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nature05674","article-title":"Myc deletion rescues apc deficiency in the small intestine","volume":"446","author":"Sansom","year":"2007","journal-title":"Nature"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"38892","DOI":"10.18632\/oncotarget.6476","article-title":"Ras-mapk pathway epigenetic activation in cancer: Mirnas in action","volume":"7","author":"Garinet","year":"2016","journal-title":"Oncotarget"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"6683","DOI":"10.1093\/nar\/gks324","article-title":"Negative regulation of mir-145 by c\/ebp-beta through the akt pathway in cancer cells","volume":"40","author":"Sachdeva","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1111\/acel.12469","article-title":"Metformin-mediated increase in dicer1 regulates microrna expression and cellular senescence","volume":"15","author":"Dluzen","year":"2016","journal-title":"Aging Cell"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Leclerc, G.M., Leclerc, G.J., Kuznetsov, J.N., DeSalvo, J., and Barredo, J.C. (2013). Metformin induces apoptosis through ampk-dependent inhibition of upr signaling in all lymphoblasts. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074420"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"7391","DOI":"10.1038\/sj.onc.1209100","article-title":"Akt signaling in normal and malignant cells","volume":"24","author":"Testa","year":"2005","journal-title":"Oncogene"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s11523-011-0167-8","article-title":"Mechanisms of mtor inhibitor resistance in cancer therapy","volume":"6","author":"Carew","year":"2011","journal-title":"Target. Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"757","DOI":"10.2147\/CIA.S158513","article-title":"Oxidative stress, aging, and diseases","volume":"13","author":"Liguori","year":"2018","journal-title":"Clin. Interv. Aging"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1700","DOI":"10.3892\/etm.2016.3143","article-title":"Metformin induces apoptosis via a mitochondria-mediated pathway in human breast cancer cells in vitro","volume":"11","author":"Gao","year":"2016","journal-title":"Exp. Ther. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1248\/bpb.b19-00474","article-title":"Metformin induces oxidative stress-mediated apoptosis without the blockade of glycolysis in h4iie hepatocellular carcinoma cells","volume":"42","author":"Park","year":"2019","journal-title":"Biol. Pharm. Bull."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"15992","DOI":"10.1038\/s41598-017-16149-z","article-title":"Metformin transiently inhibits colorectal cancer cell proliferation as a result of either ampk activation or increased ros production","volume":"7","author":"Mogavero","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/s41419-018-0429-9","article-title":"Differentiation by nerve growth factor (ngf) involves mechanisms of crosstalk between energy homeostasis and mitochondrial remodeling","volume":"9","author":"Martorana","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.4103\/0366-6999.181965","article-title":"Aberrant alternative polyadenylation is responsible for survivin up-regulation in ovarian cancer","volume":"129","author":"He","year":"2016","journal-title":"Chin. Med. J."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00432-015-1998-y","article-title":"Role of dihydrotestosterone (dht) on tgf-beta1 signaling pathway in epithelial ovarian cancer cells","volume":"142","author":"Gabler","year":"2016","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1091\/mbc.e08-09-0939","article-title":"Caveolin-1-mediated suppression of cyclooxygenase-2 via a beta-catenin-tcf\/lef-dependent transcriptional mechanism reduced prostaglandin e2 production and survivin expression","volume":"20","author":"Rodriguez","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"377","DOI":"10.4067\/S0716-97602009000300012","article-title":"A semi-quantitative assay to screen for angiogenic compounds and compounds with angiogenic potential using the ea.Hy926 endothelial cell line","volume":"42","author":"Aranda","year":"2009","journal-title":"Biol. Res."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/13\/10\/315\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:22:10Z","timestamp":1760178130000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/13\/10\/315"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,16]]},"references-count":94,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["ph13100315"],"URL":"https:\/\/doi.org\/10.3390\/ph13100315","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,16]]}}}