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The anticancer potential of metformin on prostate cancer

Prostate Cancer and Prostatic Diseases volume 22, pages 351–361 (2019)Cite this article

Subjects

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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References

  1. 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.

    Article  CAS  Google Scholar 

  2. 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.

    Article  CAS  Google Scholar 

  3. 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.

    Article  CAS  Google Scholar 

  4. 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.

    Article  Google Scholar 

  5. Patel AR, Klein EA. Risk factors for prostate cancer. Nat Clin Pract Urol. 2009;6:87–95.

    Article  Google Scholar 

  6. 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.

    Article  CAS  Google Scholar 

  7. Elo JP, Visakorpi T. Molecular genetics of prostate cancer. Ann Med. 2001;33:130–41.

    Article  CAS  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. 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.

    Article  Google Scholar 

  11. Kolonel LN, Altshuler D, Henderson BE. The multiethnic cohort study: exploring genes, lifestyle and cancer risk. Nat Rev Cancer. 2004;4:519–27.

    Article  CAS  Google Scholar 

  12. Brawley OW. Prostate cancer epidemiology in the United States. World J Urol. 2012;30:195–200.

    Article  Google Scholar 

  13. 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

    Article  Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

  15. 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.

    Article  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. 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.

    Article  Google Scholar 

  18. 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.

    CAS  PubMed  Google Scholar 

  19. Whitburn J, Edwards CM, Sooriakumaran P. Metformin and prostate cancer: a new role for an old drug. Curr Urol Rep. 2017;18:46.

    Article  Google Scholar 

  20. 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.

    Article  CAS  Google Scholar 

  21. 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.

    Article  Google Scholar 

  22. 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.

    Article  CAS  Google Scholar 

  23. 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.

    Article  Google Scholar 

  24. 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.

    Article  CAS  Google Scholar 

  25. Hankinson SJ, Fam M, Patel NN. A review for clinicians: prostate cancer and the antineoplastic properties of metformin. Urol Oncol. 2017;35:21–9.

    Article  CAS  Google Scholar 

  26. 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.

    Article  Google Scholar 

  27. 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.

    Article  CAS  Google Scholar 

  28. Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol. 2009;196:65–80.

    Article  CAS  Google Scholar 

  29. Kasznicki J, Sliwinska A, Drzewoski J. Metformin in cancer prevention and therapy. Ann Transl Med. 2014;2:57.

    PubMed  PubMed Central  Google Scholar 

  30. 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.

    Article  CAS  Google Scholar 

  31. 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.

    Article  CAS  Google Scholar 

  32. Rayet B, Gelinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 1999;18:6938–47.

    Article  CAS  Google Scholar 

  33. 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.

    Article  CAS  Google Scholar 

  34. 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.

    Article  Google Scholar 

  35. 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.

    Article  CAS  Google Scholar 

  36. 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.

    PubMed  PubMed Central  Google Scholar 

  37. Kypta RM, Waxman J. Wnt/beta-catenin signalling in prostate cancer. Nat Rev Urol. 2012;9:418–28.

    Article  CAS  Google Scholar 

  38. 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.

    Article  CAS  Google Scholar 

  39. 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.

    Article  CAS  Google Scholar 

  40. Gronich N, Rennert G. Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates. Nat Rev Clin Oncol. 2013;10:625–42.

    Article  CAS  Google Scholar 

  41. 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.

    Article  Google Scholar 

  42. Mayer MJ, Klotz LH, Venkateswaran V. Metformin and prostate cancer stem cells: a novel therapeutic target. Prostate Cancer Prostatic Dis. 2015;18:303–9.

    Article  CAS  Google Scholar 

  43. Jaworska D, Krol W, Szliszka E. Prostate cancer stem cells: research advances. Int J Mol Sci. 2015;16:27433–49.

    Article  CAS  Google Scholar 

  44. 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.

    Article  CAS  Google Scholar 

  45. 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.

    Article  CAS  Google Scholar 

  46. 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.

    Article  CAS  Google Scholar 

  47. 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.

    Article  CAS  Google Scholar 

  48. 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.

    Article  CAS  Google Scholar 

  49. 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.

    Article  CAS  Google Scholar 

  50. 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.

    Article  CAS  Google Scholar 

  51. 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.

    Article  CAS  Google Scholar 

  52. 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.

    Article  CAS  Google Scholar 

  53. 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.

    Article  Google Scholar 

  54. 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.

    Article  CAS  Google Scholar 

  55. 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.

    Article  Google Scholar 

  56. 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.

    Article  CAS  Google Scholar 

  57. 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.

    Article  CAS  Google Scholar 

  58. 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.

    CAS  PubMed  Google Scholar 

  59. 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.

    Article  CAS  Google Scholar 

  60. 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.

    Article  CAS  Google Scholar 

  61. 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.

    Article  Google Scholar 

  62. 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.

    Article  CAS  Google Scholar 

  63. 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.

    Article  Google Scholar 

  64. 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.

    Article  Google Scholar 

  65. 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.

    Article  CAS  Google Scholar 

  66. 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.

    Article  CAS  Google Scholar 

  67. 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.

    Article  CAS  Google Scholar 

  68. 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.

    Article  Google Scholar 

  69. 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.

    Article  CAS  Google Scholar 

  70. 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.

  71. 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.

    Article  CAS  Google Scholar 

  72. 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.

    Article  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Stony Brook Medicine, Stony Brook, NY, USA

    Saher Zaidi, Jason Gandhi & Sardar Ali Khan

  2. Medical Student Research Institute, St. George’s University School of Medicine, Grenada, Grenada

    Jason Gandhi

  3. Department of Internal Medicine, Stony Brook Southampton Hospital, Southampton, NY, USA

    Gunjan Joshi

  4. Foley Plaza Medical, New York, NY, USA

    Noel L. Smith

  5. Department of Urology, Stony Brook Medicine, Stony Brook, NY, USA

    Sardar Ali Khan

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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

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