Prostate cancer (PCa) is characterized as the most frequent type of cancer in males. Recent research has suggested patients who have diabetes mellitus taking metformin (MF) have a lower risk of PCa. MF has antineoplastic effects such as adenosine monophosphate-activated protein kinase (AMPK)-dependent and independent mechanisms, suppression of androgen signaling pathway, and alterations of insulin-like growth factor-1 (IGF-1) signaling pathways that cause the growth and proliferation of PCa. Based on epidemiological factors, patients with diabetes mellitus may have a protective effect on PCa.
A literature search on MEDLINE® was conducted using a combined query of “prostate cancer” and "metformin" to yield publications unveiling the mechanisms of action, biological effects, epidemiological evidence, and research advances of MF with respect to PCa.
Evidence has shown that MF has multiple antineoplastic effects through AMPK-dependent and independent mechanisms, the alteration of IGF-1 signaling pathways, suppression of the androgen receptor pathway, inhibition of the mTOR pathway, and lipogenesis. Conduction of meta-analysis suggests mortality benefit to patients who exhibit PCa when taking MF. Clinical trials have shown evidence, demonstrating MF to improving significantly.
Herewith we review the literature regarding the numerous mechanisms of action of MF on PCa in order to decrease or repress the growth, proliferation, and differentiation of PCa cells. We analyze the molecular impacts of MF as well as adjunct therapies such as androgen deprivation therapy, aspirin, statin, or chemotherapy, proposing that MF may have a future role in the treatment protocol of PCa whether as a monotherapy or in combination with other drugs.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $24.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Sarmento-Cabral A, L-López F, Gahete MD, Castano JP, Luque RM. Metformin reduces prostate tumor growth, in a diet-dependent manner, by modulating multiple signaling pathways. Mol Cancer Res. 2017;15:862–74.
Sin HY, Kim JY, Jung KH. Total cholesterol, high density lipoprotein and triglyceride for cardiovascular disease in elderly patients treated with metformin. Arch Pharm Res. 2011;34:99–107.
Romero R, Erez O, Huttemann M, Maymon E, Panaitescu B, Conde-Agudelo A, et al. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol. 2017;217:282–302.
Henderson D, Frieson D, Zuber J, Solomon SS. Metformin has positive therapeutic effects in colon cancer and lung cancer. Am J Med Sci. 2017;354:246–51.
Patel AR, Klein EA. Risk factors for prostate cancer. Nat Clin Pract Urol. 2009;6:87–95.
Goh CL, Schumacher FR, Easton D, Muir K, Henderson B, Kote-Jarai Z, et al. Genetic variants associated with predisposition to prostate cancer and potential clinical implications. J Intern Med. 2012;271:353–65.
Elo JP, Visakorpi T. Molecular genetics of prostate cancer. Ann Med. 2001;33:130–41.
Edwards SM, Kote-Jarai Z, Meitz J, Hamoudi R, Hope Q, Osin P, et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet. 2003;72:1–12.
Nelson WG, De Marzo AM, DeWeese TL, Isaacs WB. The role of inflammation in the pathogenesis of prostate cancer. J Urol. 2004;172:S6–11.
Ben-Shlomo Y, Evans S, Ibrahim F, Patel B, Anson K, Chinegwundoh F, et al. The risk of prostate cancer amongst black men in the United Kingdom: the PROCESS cohort study. Eur Urol. 2008;53:99–105.
Kolonel LN, Altshuler D, Henderson BE. The multiethnic cohort study: exploring genes, lifestyle and cancer risk. Nat Rev Cancer. 2004;4:519–27.
Brawley OW. Prostate cancer epidemiology in the United States. World J Urol. 2012;30:195–200.
Zingales V, Raffaele M, Zanghi A, Barbagallo I, Vanella L, Distefano A. Metformin: a bridge between diabetes and prostate cancer. Front Oncol. 2017;7:243
Sui X, Xu Y, Wang X, Han W, Pan H, Xiao M. Metformin: a novel but controversial drug in cancer prevention and treatment. Mol Pharm. 2015;12:3783–91.
Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330:1304–5.
Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009;32:1620–5.
Raval AD, Mattes MD, Madhavan S, Pan X, Wei W, Sambamoorthi U. Association between metformin use and cancer stage at diagnosis among elderly medicare beneficiaries with preexisting type 2 diabetes mellitus and incident prostate cancer. J Diabetes Res. 2016;2016:2656814.
Chien SW, Kuo DY, Liao JM, Wang PS, Yu CH. Growth modulation of diabetic factors and antidiabetic drugs on prostate cancer cell lines. Chin J Physiol. 2016;59:109–18.
Whitburn J, Edwards CM, Sooriakumaran P. Metformin and prostate cancer: a new role for an old drug. Curr Urol Rep. 2017;18:46.
White-Al Habeeb NM, Garcia J, Fleshner N, Bapat B. Metformin elicits antitumor effects and downregulates the histone methyltransferase multiple myeloma SET domain (MMSET) in prostate cancer cells. Prostate. 2016;76:1507–18.
Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, et al. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 2011;71:4366–72.
Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell. 2011;19:575–86.
Gonnissen A, Isebaert S, McKee CM, Muschel RJ, Haustermans K. The effect of metformin and GANT61 combinations on the radiosensitivity of prostate cancer cells. Int J Mol Sci. 2017;18:E399.
Tong D, Liu Q, Liu G, Xu J, Lan W, Jiang Y, et al. Metformin inhibits castration-induced EMT in prostate cancer by repressing COX2/PGE2/STAT3 axis. Cancer Lett. 2017;389:23–32.
Hankinson SJ, Fam M, Patel NN. A review for clinicians: prostate cancer and the antineoplastic properties of metformin. Urol Oncol. 2017;35:21–9.
Chong RW, Vasudevan V, Zuber J, Solomon SS. Metformin has a positive therapeutic effect on prostate cancer in patients with type 2 diabetes mellitus. Am J Med Sci. 2016;351:416–9.
Lee SY, Song CH, Xie YB, Jung C, Choi HS, Lee K. SMILE upregulated by metformin inhibits the function of androgen receptor in prostate cancer cells. Cancer Lett. 2014;354:390–7.
Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol. 2009;196:65–80.
Kasznicki J, Sliwinska A, Drzewoski J. Metformin in cancer prevention and therapy. Ann Transl Med. 2014;2:57.
Biernacka KM, Persad RA, Bahl A, Gillatt D, Holly JM, Perks CM. Hyperglycaemia-induced resistance to Docetaxel is negated by metformin: a role for IGFBP-2. Endocr Relat Cancer. 2017;24:17–30.
Li R, Pourpak A, Morris SW. Inhibition of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase as a novel cancer therapy approach. J Med Chem. 2009;52:4981–5004.
Rayet B, Gelinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 1999;18:6938–47.
Kim HG, Hien TT, Han EH, Hwang YP, Choi JH, Kang KW, et al. Metformin inhibits P-glycoprotein expression via the NF-kappaB pathway and CRE transcriptional activity through AMPK activation. Br J Pharmacol. 2011;162:1096–108.
Nordstrom T, Clements M, Karlsson R, Adolfsson J, Gronberg H. The risk of prostate cancer for men on aspirin, statin or antidiabetic medications. Eur J Cancer. 2015;51:725–33.
Yue W, Yang CS, DiPaola RS, Tan XL. Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment. Cancer Prev Res. 2014;7:388–97.
Yue W, Zheng X, Lin Y, Yang CS, Xu Q, Carpizo D, et al. Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2. Oncotarget. 2015;6:21208–24.
Kypta RM, Waxman J. Wnt/beta-catenin signalling in prostate cancer. Nat Rev Urol. 2012;9:418–28.
Lehman DM, Lorenzo C, Hernandez J, Wang CP. Statin use as a moderator of metformin effect on risk for prostate cancer among type 2 diabetic patients. Diabetes Care. 2012;35:1002–7.
Gash KJ, Chambers AC, Cotton DE, Williams AC, Thomas MG. Potentiating the effects of radiotherapy in rectal cancer: the role of aspirin, statins and metformin as adjuncts to therapy. Br J Cancer. 2017;117:210–9.
Gronich N, Rennert G. Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates. Nat Rev Clin Oncol. 2013;10:625–42.
Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, et al. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res. 2010;70:2465–75.
Mayer MJ, Klotz LH, Venkateswaran V. Metformin and prostate cancer stem cells: a novel therapeutic target. Prostate Cancer Prostatic Dis. 2015;18:303–9.
Jaworska D, Krol W, Szliszka E. Prostate cancer stem cells: research advances. Int J Mol Sci. 2015;16:27433–49.
Saha A, Blando J, Tremmel L, DiGiovanni J. Effect of metformin, rapamycin, and their combination on growth and progression of prostate tumors in HiMyc mice. Cancer Prev Res. 2015;8:597–606.
Luo Q, Hu D, Hu S, Yan M, Sun Z, Chen F. In vitro and in vivo anti-tumor effect of metformin as a novel therapeutic agent in human oral squamous cell carcinoma. BMC Cancer. 2012;12:517.
Zhang J, Shen C, Wang L, Ma Q, Xia P, Qi M, et al. Metformin inhibits epithelial–mesenchymal transition in prostate cancer cells: involvement of the tumor suppressor miR30a and its target gene SOX4. Biochem Biophys Res Commun. 2014;452:746–52.
Sun S, Gong F, Liu P, Miao Q. Metformin combined with quercetin synergistically repressed prostate cancer cells via inhibition of VEGF/PI3K/Akt signaling pathway. Gene. 2018;664:50–7.
Landim BC, de Jesus MM, Bosque BP, Zanon RG, da Silva CV, Goes RM, et al. Stimulating effect of palmitate and insulin on cell migration and proliferation in PNT1A and PC3 prostate cells: counteracting role of metformin. Prostate. 2018;78:731–42.
Tran LNK, Kichenadasse G, Butler LM, Centenera MM, Morel KL, Ormsby RJ, et al. The combination of metformin and valproic acid induces synergistic apoptosis in the presence of p53 and androgen signaling in prostate cancer. Mol Cancer Ther. 2017;16:2689–700.
Yu T, Wang C, Yang J, Guo Y, Wu Y, Li X. Metformin inhibits SUV39H1-mediated migration of prostate cancer cells. Oncogenesis. 2017;6:e324.
Yang J, Wei J, Wu Y, Wang Z, Guo Y, Lee P, et al. Metformin induces ER stress-dependent apoptosis through miR-708-5p/NNAT pathway in prostate cancer. Oncogenesis. 2015;4:e158.
Wang ZS, Huang HR, Zhang LY, Kim S, He Y, Li DL, et al. Mechanistic study of inhibitory effects of metformin and atorvastatin in combination on prostate cancer cells in vitro and in vivo. Biol Pharm Bull. 2017;40:1247–54.
Loubiere C, Goiran T, Laurent K, Djabari Z, Tanti JF, Bost F. Metformin-induced energy deficiency leads to the inhibition of lipogenesis in prostate cancer cells. Oncotarget. 2015;6:15652–61.
Clements A, Gao B, Yeap SH, Wong MK, Ali SS, Gurney H. Metformin in prostate cancer: two for the price of one. Ann Oncol. 2011;22:2556–60.
Haggstrom C, Van Hemelrijck M, Zethelius B, Robinson D, Grundmark B, Holmberg L, et al. Prospective study of type 2 diabetes mellitus, anti-diabetic drugs and risk of prostate cancer. Int J Cancer. 2017;140:611–7.
Wang CF, Zhang G, Zhao LJ, Qi WJ, Li XP, Wang JL, et al. Overexpression of the insulin receptor isoform A promotes endometrial carcinoma cell growth. PLoS One. 2013;8:e69001.
Zordoky BN, Bark D, Soltys CL, Sung MM, Dyck JR. The anti-proliferative effect of metformin in triple-negative MDA-MB-231 breast cancer cells is highly dependent on glucose concentration: implications for cancer therapy and prevention. Biochim Biophys Acta. 2014;1840:1943–57.
Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del Barco S, Martin-Castillo B, Lopez-Bonet E, et al. The anti-diabetic drug metformin suppresses the metastasis-associated protein CD24 in MDA-MB-468 triple-negative breast cancer cells. Oncol Rep. 2011;25:135–40.
Rothermundt C, Hayoz S, Templeton AJ, Winterhalder R, Strebel RT, Bartschi D, et al. Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09). Eur Urol. 2014;66:468–74.
Margel D, Urbach DR, Lipscombe LL, Bell CM, Kulkarni G, Austin PC, et al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J Clin Oncol. 2013;31:3069–75.
Kaushik D, Karnes RJ, Eisenberg MS, Rangel LJ, Carlson RE, Bergstralh EJ. Effect of metformin on prostate cancer outcomes after radical prostatectomy. Urol Oncol. 2014;32:43e.1.
Allott EH, Abern MR, Gerber L, Keto CJ, Aronson WJ, Terris MK, et al. Metformin does not affect risk of biochemical recurrence following radical prostatectomy: results from the SEARCH database. Prostate Cancer Prostatic Dis. 2013;16:391–7.
Murtola TJ, Tammela TL, Lahtela J, Auvinen A. Antidiabetic medication and prostate cancer risk: a population-based case-control study. Am J Epidemiol. 2008;168:925–31.
Wright JL, Stanford JL. Metformin use and prostate cancer in Caucasian men: results from a population-based case-control study. Cancer Causes Control. 2009;20:1617–22.
Danzig MR, Kotamarti S, Ghandour RA, Rothberg MB, Dubow BP, Benson MC, et al. Synergism between metformin and statins in modifying the risk of biochemical recurrence following radical prostatectomy in men with diabetes. Prostate Cancer Prostatic Dis. 2015;18:63–8.
Zannella VE, Dal Pra A, Muaddi H, McKee TD, Stapleton S, Sykes J, et al. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin Cancer Res. 2013;19:6741–50.
Spratt DE, Zhang C, Zumsteg ZS, Pei X, Zhang Z, Zelefsky MJ. Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality. Eur Urol. 2013;63:709–16.
He XX, Tu SM, Lee MH, Yeung SC. Thiazolidinediones and metformin associated with improved survival of diabetic prostate cancer patients. Ann Oncol. 2011;22:2640–5.
Nobes JP, Langley SE, Klopper T, Russell-Jones D, Laing RW. A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy. BJU Int. 2012;109:1495–502.
Clinicaltrials.gov. U.S. National Library of Medicine, U.S. National Institutes of Health, U.S. Department of Health and Human Services: United States; 2017.
Richards KA, Liou JI, Cryns VL, Downs TM, Abel EJ, Jarrard DF. Metformin use is associated with improved survival in patients with advanced prostate cancer on androgen deprivation therapy. J Urol. 2018. https://doi.org/10.1016/j.juro.2018.06.031.
Dell’Atti L, Galosi AB. The impact of metformin use on the risk of prostate cancer after prostate biopsy in patients with high grade intraepithelial neoplasia. Int Braz J Urol. 2018;44:69–74.
The authors are thankful to Drs. Kelly Warren, Inefta Reid, Todd Miller, and Peter Brink for departmental support, as well as Mrs. Wendy Isser and Ms. Grace Garey for literature retrieval.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Zaidi, S., Gandhi, J., Joshi, G. et al. The anticancer potential of metformin on prostate cancer. Prostate Cancer Prostatic Dis 22, 351–361 (2019). https://doi.org/10.1038/s41391-018-0085-2
Racial/ethnic disparities in patient experiences with care and Gleason score at diagnosis of prostate cancer: a SEER-CAHPS study
Cancer Causes & Control (2022)
Brain Boron Level, DNA Content, and Myeloperoxidase Activity of Metformin-Treated Rats in Diabetes and Prostate Cancer Model
Biological Trace Element Research (2022)
Prostate Cancer and Prostatic Diseases (2021)
British Journal of Cancer (2021)