{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:58:14Z","timestamp":1790683094337,"version":"4.1.0"},"reference-count":85,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T00:00:00Z","timestamp":1605139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2020R1F1A1073833"],"award-info":[{"award-number":["2020R1F1A1073833"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Gangnam Severance Hospital Prostate Cancer Center Research Committee","award":["7523110"],"award-info":[{"award-number":["7523110"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metformin, an oral biguanide used for first-line treatment of type 2 diabetes mellitus, has attracted attention for its anti-proliferative and anti-cancer effects in several solid tumors, including prostate cancer (PCa). Liver kinase B1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK) activation, inhibition of the mammalian target of rapamycin (mTOR) activity and protein synthesis, induction of apoptosis and autophagy by p53 and p21, and decreased blood insulin level have been suggested as direct anti-cancer mechanisms of metformin. Research has shown that PCa development and progression are associated with metabolic syndrome and its components. Therefore, reduction in the risk of PCa and improvement in survival in metformin users may be the results of the direct anti-cancer mechanisms of the drug or the secondary effects from improvement of metabolic syndrome. In contrast, some research has suggested that there is no association between metformin use and PCa incidence or survival. In this comprehensive review, we summarize updated evidence on the relationship between metformin use and oncological effects in patients with PCa. We also highlight ongoing clinical trials evaluating metformin as an adjuvant therapy in novel drug combinations in various disease settings.<\/jats:p>","DOI":"10.3390\/ijms21228540","type":"journal-article","created":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T10:00:32Z","timestamp":1605175232000},"page":"8540","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Current Status and Application of Metformin for Prostate Cancer: A Comprehensive Review"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1996-6249","authenticated-orcid":false,"given":"Hyun Kyu","family":"Ahn","sequence":"first","affiliation":[{"name":"Department of Urology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06229, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Hwa","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Urology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06229, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7303-6256","authenticated-orcid":false,"given":"Kyo Chul","family":"Koo","sequence":"additional","affiliation":[{"name":"Department of Urology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06229, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Franciosi, M., Lucisano, G., Lapice, E., Strippoli, G.F., Pellegrini, F., and Nicolucci, A. (2013). Metformin therapy and risk of cancer in patients with type 2 diabetes: Systematic review. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0071583"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1111\/j.1749-6632.2010.05679.x","article-title":"Metformin in polycystic ovary syndrome","volume":"1205","author":"Economou","year":"2010","journal-title":"Ann. N. Y. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1634\/theoncologist.2013-0111","article-title":"Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: A systematic review and meta-analysis","volume":"18","author":"Yin","year":"2013","journal-title":"Oncologist"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/sj.bjc.6600526","article-title":"Serum insulin level, disease stage, prostate specific antigen (psa) and gleason score in prostate cancer","volume":"87","author":"Lehrer","year":"2002","journal-title":"Br. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1016\/S1470-2045(08)70235-3","article-title":"Prediagnostic body-mass index, plasma c-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: A long-term survival analysis","volume":"9","author":"Ma","year":"2008","journal-title":"Lancet Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1038\/s41598-018-38285-w","article-title":"The effect of metformin therapy on incidence and prognosis in prostate cancer: A systematic review and meta-analysis","volume":"9","author":"He","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.canep.2012.12.009","article-title":"Association of metformin use with cancer incidence and mortality: A meta-analysis","volume":"37","author":"Zhang","year":"2013","journal-title":"Cancer Epidemiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1111\/dom.12267","article-title":"The prognostic value of metformin for cancer patients with concurrent diabetes: A systematic review and meta-analysis","volume":"16","author":"Zhang","year":"2014","journal-title":"Diabetes Obes. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.prnil.2019.10.003","article-title":"Prognostic significance of diabetes mellitus and dyslipidemia in men receiving androgen-deprivation therapy for metastatic prostate cancer","volume":"7","author":"Hirata","year":"2019","journal-title":"Prostate Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.prnil.2017.03.004","article-title":"Looking to the metabolic landscapes for prostate health monitoring","volume":"5","author":"Kim","year":"2017","journal-title":"Prostate Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.eururo.2011.11.013","article-title":"The correlation between metabolic syndrome and prostatic diseases","volume":"61","author":"Aronson","year":"2012","journal-title":"Eur. Urol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1158\/1055-9965.1646.13.10","article-title":"Metabolic syndrome and the risk of prostate cancer in finnish men: A population-based study","volume":"13","author":"Laukkanen","year":"2004","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1093\/aje\/kwj284","article-title":"Metabolic syndrome predicts prostate cancer in a cohort of middle-aged norwegian men followed for 27 years","volume":"164","author":"Wisloff","year":"2006","journal-title":"Am. J. Epidemiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.urology.2009.03.013","article-title":"Racial differences in risk of prostate cancer associated with metabolic syndrome","volume":"74","author":"Nock","year":"2009","journal-title":"Urology"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Collaborative Normal-Tension Glaucoma Study Group (1998). Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Am. J. Ophthalmol., 126, 487\u2013497.","DOI":"10.1016\/S0002-9394(98)00223-2"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6199","DOI":"10.1002\/cncr.27677","article-title":"Prospective study on metabolic factors and risk of prostate cancer","volume":"118","author":"Haggstrom","year":"2012","journal-title":"Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/nrurol.2018.8","article-title":"A stage-dependent link between metabolic syndrome components and incident prostate cancer","volume":"15","author":"Hammarsten","year":"2018","journal-title":"Nat. Rev. Urol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1093\/aje\/kwj320","article-title":"The metabolic syndrome is associated with reduced risk of prostate cancer","volume":"164","author":"Tande","year":"2006","journal-title":"Am. J. Epidemiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1002\/ijc.25171","article-title":"Blood pressure, body size and prostate cancer risk in the swedish construction workers cohort","volume":"127","author":"Stocks","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1592\/phco.28.12.1511","article-title":"Increased risk of metabolic syndrome, diabetes mellitus, and cardiovascular disease in men receiving androgen deprivation therapy for prostate cancer","volume":"28","author":"Kintzel","year":"2008","journal-title":"Pharmacotherapy"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.eururo.2014.07.010","article-title":"Adverse effects of androgen deprivation therapy and strategies to mitigate them","volume":"67","author":"Nguyen","year":"2015","journal-title":"Eur. Urol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5754","DOI":"10.1158\/0008-5472.CAN-10-2470","article-title":"Insulin increases de novo steroidogenesis in prostate cancer cells","volume":"71","author":"Lubik","year":"2011","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1093\/annonc\/mdq443","article-title":"Presence of the metabolic syndrome is associated with shorter time to castration-resistant prostate cancer","volume":"22","author":"Flanagan","year":"2011","journal-title":"Ann. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10804","DOI":"10.1158\/0008-5472.CAN-07-2310","article-title":"Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells","volume":"67","author":"Dowling","year":"2007","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.cmet.2004.12.003","article-title":"Amp-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism","volume":"1","author":"Kahn","year":"2005","journal-title":"Cell Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nrc3967","article-title":"Adiposity and cancer risk: New mechanistic insights from epidemiology","volume":"15","author":"Renehan","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.2337\/diabetes.53.4.1052","article-title":"Thiazolidinediones, like metformin, inhibit respiratory complex i: A common mechanism contributing to their antidiabetic actions?","volume":"53","author":"Brunmair","year":"2004","journal-title":"Diabetes"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10269","DOI":"10.1158\/0008-5472.CAN-06-1500","article-title":"Metformin is an amp kinase-dependent growth inhibitor for breast cancer cells","volume":"66","author":"Zakikhani","year":"2006","journal-title":"Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S0092-8674(03)00929-2","article-title":"Tsc2 mediates cellular energy response to control cell growth and survival","volume":"115","author":"Inoki","year":"2003","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"291","DOI":"10.2217\/fon.09.9","article-title":"Targeting the mtor pathway using deforolimus in cancer therapy","volume":"5","author":"Mahalingam","year":"2009","journal-title":"Future Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.cmet.2010.03.014","article-title":"Metformin, independent of ampk, inhibits mtorc1 in a rag gtpase-dependent manner","volume":"11","author":"Kalender","year":"2010","journal-title":"Cell Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nrm3311","article-title":"Ampk: A nutrient and energy sensor that maintains energy homeostasis","volume":"13","author":"Hardie","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1126\/science.1120781","article-title":"The kinase lkb1 mediates glucose homeostasis in liver and therapeutic effects of metformin","volume":"310","author":"Shaw","year":"2005","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e6888","DOI":"10.1097\/MD.0000000000006888","article-title":"Meta-analysis of studies using metformin as a reducer for liver cancer risk in diabetic patients","volume":"96","author":"Ma","year":"2017","journal-title":"Medicine (Baltimore)"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1200\/JCO.2011.36.2723","article-title":"Insulin- and obesity-related variables in early-stage breast cancer: Correlations and time course of prognostic associations","volume":"30","author":"Goodwin","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1200\/JCO.2008.17.9945","article-title":"Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer","volume":"27","author":"Wolpin","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1002\/bies.20151","article-title":"Insulin and its receptor: Structure, function and evolution","volume":"26","year":"2004","journal-title":"Bioessays"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"F9","DOI":"10.1530\/ERC-12-0105","article-title":"Diabetes and pancreatic cancer","volume":"19","author":"Cui","year":"2012","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1096\/fj.11-192088","article-title":"Caveolin-1 is essential for metformin inhibitory effect on igf1 action in non-small-cell lung cancer cells","volume":"26","author":"Salani","year":"2012","journal-title":"FASEB J."},{"key":"ref_40","first-page":"204","article-title":"Caveolin-1 and polymerase i and transcript release factor: New players in insulin-like growth factor-i receptor signaling","volume":"36","author":"Hamoudane","year":"2013","journal-title":"J. Endocrinol. Invest."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"R461","DOI":"10.1530\/ERC-14-0284","article-title":"Metformin, cancer and glucose metabolism","volume":"21","author":"Salani","year":"2014","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrc3038","article-title":"Otto warburg\u2019s contributions to current concepts of cancer metabolism","volume":"11","author":"Koppenol","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1038\/srep02070","article-title":"Metformin impairs glucose consumption and survival in calu-1 cells by direct inhibition of hexokinase-ii","volume":"3","author":"Salani","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1007\/s11934-017-0693-8","article-title":"Metformin and prostate cancer: A new role for an old drug","volume":"18","author":"Whitburn","year":"2017","journal-title":"Curr. Urol. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/s10555-013-9474-0","article-title":"Androgen receptor signaling in prostate cancer","volume":"33","author":"Culig","year":"2014","journal-title":"Cancer Metastasis Rev."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Demir, U., Koehler, A., Schneider, R., Schweiger, S., and Klocker, H. (2014). Metformin anti-tumor effect via disruption of the mid1 translational regulator complex and ar downregulation in prostate cancer cells. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-52"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1002\/pros.23000","article-title":"Metformin represses androgen-dependent and androgen-independent prostate cancers by targeting androgen receptor","volume":"75","author":"Wang","year":"2015","journal-title":"Prostate"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.eururo.2014.04.027","article-title":"Metformin use and prostate cancer risk","volume":"66","author":"Preston","year":"2014","journal-title":"Eur. Urol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1080\/21681805.2016.1271353","article-title":"Antidiabetic drug use and prostate cancer risk in the finnish randomized study of screening for prostate cancer","volume":"51","author":"Haring","year":"2017","journal-title":"Scand. J. Urol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"119","DOI":"10.2337\/dc11-0857","article-title":"Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: Results from a large population-based follow-up study","volume":"35","author":"Ruiter","year":"2012","journal-title":"Diabetes Care"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1158\/1940-6207.CAPR-15-0141","article-title":"Metformin use and risk of prostate cancer: Results from the reduce study","volume":"8","author":"Feng","year":"2015","journal-title":"Cancer Prev. Res. (Phila)"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/pcan.2016.65","article-title":"Metformin and the risk of prostate cancer across racial\/ethnic groups: A population-based cohort study","volume":"20","author":"Chen","year":"2017","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1158\/1940-6207.CAPR-15-0425","article-title":"Metformin for reducing racial\/ethnic difference in prostate cancer incidence for men with type ii diabetes","volume":"9","author":"Wang","year":"2016","journal-title":"Cancer Prev. Res. (Phila)"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2656814","DOI":"10.1155\/2016\/2656814","article-title":"Association between metformin use and cancer stage at diagnosis among elderly medicare beneficiaries with preexisting type 2 diabetes mellitus and incident prostate cancer","volume":"2016","author":"Raval","year":"2016","journal-title":"J. Diabetes Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.ejca.2015.02.003","article-title":"The risk of prostate cancer for men on aspirin, statin or antidiabetic medications","volume":"51","author":"Nordstrom","year":"2015","journal-title":"Eur. J. Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1097\/CEJ.0b013e3283656394","article-title":"Type 2 diabetes mellitus, glycemic control, and cancer risk","volume":"23","author":"Onitilo","year":"2014","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1016\/j.ejca.2014.08.007","article-title":"Metformin significantly reduces incident prostate cancer risk in taiwanese men with type 2 diabetes mellitus","volume":"50","author":"Tseng","year":"2014","journal-title":"Eur. J. Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Chen, C.B., Eskin, M., Eurich, D.T., Majumdar, S.R., and Johnson, J.A. (2018). Metformin, asian ethnicity and risk of prostate cancer in type 2 diabetes: A systematic review and meta-analysis. BMC Cancer, 18.","DOI":"10.1186\/s12885-017-3934-9"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1111\/cas.12203","article-title":"Report of the japan diabetes society\/japanese cancer association joint committee on diabetes and cancer","volume":"104","author":"Kasuga","year":"2013","journal-title":"Cancer Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.2337\/db13-1169","article-title":"Exendin-4, a glp-1 receptor agonist, attenuates prostate cancer growth","volume":"63","author":"Nomiyama","year":"2014","journal-title":"Diabetes"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Lin, C., Cai, X., Yang, W., Lv, F., Nie, L., and Ji, L. (2020). Glycemic control and the incidence of neoplasm in patients with type 2 diabetes: A meta-analysis of randomized controlled trials. Endocrine.","DOI":"10.3389\/fendo.2020.541699"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/pcan.2014.47","article-title":"Synergism between metformin and statins in modifying the risk of biochemical recurrence following radical prostatectomy in men with diabetes","volume":"18","author":"Danzig","year":"2015","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_63","first-page":"9509","article-title":"Impact of diabetes and metformin use on prostate cancer outcome of patients treated with radiation therapy: Results from a large institutional database","volume":"25","author":"Taussky","year":"2018","journal-title":"Can. J. Urol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/bju.14709","article-title":"Metformin may offer no protective effect in men undergoing external beam radiation therapy for prostate cancer","volume":"123","author":"Ranasinghe","year":"2019","journal-title":"BJU Int."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s10552-015-0687-0","article-title":"Metformin and prostate cancer mortality: A meta-analysis","volume":"27","author":"Stopsack","year":"2016","journal-title":"Cancer Causes Control"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"100449","DOI":"10.18632\/oncotarget.22117","article-title":"The impact of metformin use on survival in prostate cancer: A systematic review and meta-analysis","volume":"8","author":"Xiao","year":"2017","journal-title":"Oncotarget"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"595","DOI":"10.7314\/APJCP.2015.16.2.595","article-title":"Metformin association with lower prostate cancer recurrence in type 2 diabetes: A systematic review and meta-analysis","volume":"16","author":"Hwang","year":"2015","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1136\/amiajnl-2014-002649","article-title":"Validating drug repurposing signals using electronic health records: A case study of metformin associated with reduced cancer mortality","volume":"22","author":"Xu","year":"2015","journal-title":"J. Am. Med. Inform Assoc."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1007\/s00345-014-1426-y","article-title":"Influence of metformin use on psa values, free-to-total psa, prostate cancer incidence and grade and overall survival in a prospective screening trial (erspc aarau)","volume":"33","author":"Randazzo","year":"2015","journal-title":"World J. Urol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.eururo.2012.12.004","article-title":"Metformin and prostate cancer: Reduced development of castration-resistant disease and prostate cancer mortality","volume":"63","author":"Spratt","year":"2013","journal-title":"Eur. Urol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1158\/1055-9965.EPI-14-0056","article-title":"The use of metformin in patients with prostate cancer and the risk of death","volume":"23","author":"Bensimon","year":"2014","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.clgc.2016.08.020","article-title":"Prostate cancer patients with unmanaged diabetes or receiving insulin experience inferior outcomes and toxicities after treatment with radiation therapy","volume":"15","author":"Zaorsky","year":"2017","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.juro.2016.10.069","article-title":"The effect of metformin use during docetaxel chemotherapy on prostate cancer specific and overall survival of diabetic patients with castration resistant prostate cancer","volume":"197","author":"Mayer","year":"2017","journal-title":"J. Urol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/pcan.2016.32","article-title":"Tumor features and survival after radical prostatectomy among antidiabetic drug users","volume":"19","author":"Joentausta","year":"2016","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"254","DOI":"10.5114\/jcb.2014.45757","article-title":"Metformin is not associated with improved biochemical free survival or cause-specific survival in men with prostate cancer treated with permanent interstitial brachytherapy","volume":"6","author":"Taira","year":"2014","journal-title":"J. Contemp. Brachytherapy"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1530\/ERC-16-0095","article-title":"Hyperglycaemia-induced resistance to docetaxel is negated by metformin: A role for igfbp-2","volume":"24","author":"Biernacka","year":"2017","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.radonc.2020.06.030","article-title":"Metformin: (future) best friend of the radiation oncologist?","volume":"151","author":"Chevalier","year":"2020","journal-title":"Radiother. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3069","DOI":"10.1200\/JCO.2012.46.7043","article-title":"Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes","volume":"31","author":"Margel","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.eururo.2013.12.057","article-title":"Metformin in chemotherapy-naive castration-resistant prostate cancer: A multicenter phase 2 trial (sakk 08\/09)","volume":"66","author":"Rothermundt","year":"2014","journal-title":"Eur. Urol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Devalingam, M., Hanni, S., Christos, F., Joel, M., John, S., Paromita, D., Ofelia, R., Sureshkumar, M., John, G.K., and Michael, N.P. (2017). Metformin to treat prostate cancer (PCa) and prevent metabolic syndrome associated with androgen deprivation therapy (ADT): Results of a randomized double-blind placebo-controlled study of metformin in non-diabetic men initiating ADT for advanced PCa. J. Clin. Oncol., 35.","DOI":"10.1200\/JCO.2017.35.15_suppl.e16502"},{"key":"ref_81","unstructured":"US National Library of Medicine (2019, November 16). Metformin in Castration-Resistant Prostate Cancer, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01215032."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e323","DOI":"10.1016\/j.clgc.2018.12.009","article-title":"Impact of addition of metformin to abiraterone in metastatic castration-resistant prostate cancer patients with disease progressing while receiving abiraterone treatment (metab-pro): Phase 2 pilot study","volume":"17","author":"Mark","year":"2019","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_83","unstructured":"US National Library of Medicine (2019, November 16). Metformin Prostate Cancer Adjuvant Trial, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02176161."},{"key":"ref_84","unstructured":"US National Library of Medicine (2019, November 16). Enzalutamide and Metformin Hydrochloride in Treating Patients With Hormone-Resistant Prostate Cancer, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT0233916875."},{"key":"ref_85","unstructured":"US National Library of Medicine (2019, November 16). SAKK 08\/15\u2014PROMET\u2014Salvage Radiotherapy +\/- Metformin for Patients With Prostate Cancer After Prostatectomy, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02945813."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/22\/8540\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:32:41Z","timestamp":1760178761000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/22\/8540"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,12]]},"references-count":85,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijms21228540"],"URL":"https:\/\/doi.org\/10.3390\/ijms21228540","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,12]]}}}