Investig Clin Urol.  2016 May;57(3):157-164. 10.4111/icu.2016.57.3.157.

Potential role for metformin in urologic oncology

• Sayyid RK
• Fleshner N

• KMID: 2426489
• DOI: http://doi.org/10.4111/icu.2016.57.3.157

Abstract

Metformin is one of the most commonly used drugs worldwide. It is currently considered first-line pharmacological agent for management of diabetes mellitus type 2. Recent studies have suggested that metformin may have further benefits, especially in the field of urologic oncology. Use of metformin has been shown to be associated with decreased incidence and improved outcomes of prostate, bladder, and kidney cancer. These studies suggest that metformin does have a future role in the prevention and management of urologic malignancies. In this review, we will discuss the latest findings in this field and its implications on the management of urologic oncology patients.

Keyword

Kidney neoplasms; Metformin; Prostatic neoplasms; Urinary bladder neoplasms

MeSH Terms

Anticarcinogenic Agents/therapeutic use
Antineoplastic Agents/*therapeutic use
Carcinoma, Renal Cell/therapy
Humans
Kidney Neoplasms/therapy
Male
Metformin/*therapeutic use
Prostatic Neoplasms/therapy
Urinary Bladder Neoplasms/therapy
Urologic Neoplasms/*therapy
Anticarcinogenic Agents
Antineoplastic Agents
Metformin

Reference

1. World Health Organization. Diabetes [Internet]. Geneva: World Health Organization;2016. updated Mar 2016. cited 2016 Mar 1. Available from: http://www.who.int/mediacentre/factsheets/fs312/en/.

2. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Harper W, Clement M, Goldenberg R, Hanna A, Main A, et al. Pharmacologic management of type 2 diabetes. Can J Diabetes. 2013; 37:Suppl 1. S61–S68.

3. U.S. Food and Drug Administration. Metformin Hydrochloride Tablets [Internet]. Silver Spring (MD): U.S. Food and Drug Administration;c2016. updated Apr 29, 2016. cited 2016 Mar 1. Available from: www.fda.gov/ohrms/dockets/dailys/02/May02/053102/800471e6.pdf.

4. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005; 310:1642–1646.

5. El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000; 275:223–228.

6. Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, Bost F. Metformin in cancer therapy: a new perspective for an old antidiabetic drug? Mol Cancer Ther. 2010; 9:1092–1099.

7. Yu H, Yin L, Jiang X, Sun X, Wu J, Tian H, et al. Effect of metformin on cancer risk and treatment outcome of prostate cancer: a meta-analysis of epidemiological observational studies. PLoS One. 2014; 9:e116327.

8. Deng D, Yang Y, Tang X, Skrip L, Qiu J, Wang Y, et al. Association between metformin therapy and incidence, recurrence and mortality of prostate cancer: evidence from a meta-analysis. Diabetes Metab Res Rev. 2015; 31:595–602.

9. Tseng CH. Metformin significantly reduces incident prostate cancer risk in Taiwanese men with type 2 diabetes mellitus. Eur J Cancer. 2014; 50:2831–2837.

10. Chen-Pin W, Javier H, Lorenzo C, Downs JR, Thompson IM, Pollock B, et al. Statins and finasteride use differentially modify the impact of metformin on prostate cancer incidence in men with type 2 diabetes. Ann Transl Med Epidemiol. 2014; 1(1):pii: 1004.

11. Demir U, Koehler A, Schneider R, Schweiger S, Klocker H. Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells. BMC Cancer. 2014; 14:52.

12. Wang Y, Liu G, Tong D, Parmar H, Hasenmayer D, Yuan W, et al. Metformin represses androgen-dependent and androgen-independent prostate cancers by targeting androgen receptor. Prostate. 2015; 75:1187–1196.

13. Malaguarnera R, Sacco A, Morcavallo A, Squatrito S, Migliaccio A, Morrione A, et al. Metformin inhibits androgen-induced IGF-IR up-regulation in prostate cancer cells by disrupting membrane-initiated androgen signaling. Endocrinology. 2014; 155:1207–1221.

14. Kato H, Sekine Y, Furuya Y, Miyazawa Y, Koike H, Suzuki K. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor. Biochem Biophys Res Commun. 2015; 461:115–121.

15. Fendt SM, Bell EL, Keibler MA, Davidson SM, Wirth GJ, Fiske B, et al. Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism. Cancer Res. 2013; 73:4429–4438.

16. 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; 6:15652–15661.

17. 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; 452:746–752.

18. Ge R, Wang Z, Wu S, Zhuo Y, Otsetov AG, Cai C, et al. Metformin represses cancer cells via alternate pathways in N-cadherin expressing vs. N-cadherin deficient cells. Oncotarget. 2015; 6:28973–28987.

19. Akinyeke T, Matsumura S, Wang X, Wu Y, Schalfer ED, Saxena A, et al. Metformin targets c-MYC oncogene to prevent prostate cancer. Carcinogenesis. 2013; 34:2823–2832.

20. 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; 71:4366–4372.

21. Margel D, Urbach D, Lipscombe LL, Bell CM, Kulkarni G, Austin PC, et al. Association between metformin use and risk of prostate cancer and its grade. J Natl Cancer Inst. 2013; 105:1123–1131.

22. Zhang P, Li H, Tan X, Chen L, Wang S. Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer Epidemiol. 2013; 37:207–218.

23. Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila). 2010; 3:1451–1461.

24. Feng T, Sun X, Howard LE, Vidal AC, Gaines AR, Moreira DM, et al. Metformin use and risk of prostate cancer: results from the REDUCE study. Cancer Prev Res (Phila). 2015; 8:1055–1060.

25. Randazzo M, Beatrice J, Huber A, Grobholz R, Manka L, Wyler SF, et al. 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). World J Urol. 2015; 33:1189–1196.

26. Azoulay L, Dell'Aniello S, Gagnon B, Pollak M, Suissa S. Metformin and the incidence of prostate cancer in patients with type 2 diabetes. Cancer Epidemiol Biomarkers Prev. 2011; 20:337–344.

27. Kowall B, Stang A, Rathmann W, Kostev K. No reduced risk of overall, colorectal, lung, breast, and prostate cancer with metformin therapy in diabetic patients: database analyses from Germany and the UK. Pharmacoepidemiol Drug Saf. 2015; 24:865–874.

28. Qiu H, Rhoads GG, Berlin JA, Marcella SW, Demissie K. Initial metformin or sulphonylurea exposure and cancer occurrence among patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2013; 15:349–357.

29. Nordström T, Clements M, Karlsson R, Adolfsson J, Grönberg H. The risk of prostate cancer for men on aspirin, statin or antidiabetic medications. Eur J Cancer. 2015; 51:725–733.

30. Stopsack KH, Ziehr DR, Rider JR, Giovannucci EL. Metformin and prostate cancer mortality: a meta-analysis. Cancer Causes Control. 2016; 27:105–113.

31. Raval AD, Thakker D, Vyas A, Salkini M, Madhavan S, Sambamoorthi U. Impact of metformin on clinical outcomes among men with prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2015; 18:110–121.

32. Hwang IC, Park SM, Shin D, Ahn HY, Rieken M, Shariat SF. Metformin association with lower prostate cancer recurrence in type 2 diabetes: a systematic review and meta-analysis. Asian Pac J Cancer Prev. 2015; 16:595–600.

33. 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; 31:3069–3075.

34. Joshua AM, Zannella VE, Downes MR, Bowes B, Hersey K, Koritzinsky M, et al. A pilot 'window of opportunity' neoadjuvant study of metformin in localised prostate cancer. Prostate Cancer Prostatic Dis. 2014; 17:252–258.

35. Zhang T, Zhang L, Zhang T, Fan J, Wu K, Guan Z, et al. Metformin sensitizes prostate cancer cells to radiation through EGFR/p-DNA-PKCS in vitro and in vivo. Radiat Res. 2014; 181:641–649.

36. 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; 19:6741–6750.

37. 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; 63:709–716.

38. Colquhoun AJ, Venier NA, Vandersluis AD, Besla R, Sugar LM, Kiss A, et al. Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer. Prostate Cancer Prostatic Dis. 2012; 15:346–352.

39. Ranasinghe WK, Sengupta S, Williams S, Chang M, Shulkes A, Bolton DM, et al. The effects of nonspecific HIF1α inhibitors on development of castrate resistance and metastases in prostate cancer. Cancer Med. 2014; 3:245–251.

40. Fernandez EV, Reece KM, Ley AM, Troutman SM, Sissung TM, Price DK, et al. Dual targeting of the androgen receptor and hypoxia-inducible factor 1α pathways synergistically inhibits castration-resistant prostate cancer cells. Mol Pharmacol. 2015; 87:1006–1012.

41. 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; 18:63–68.

42. Babcook MA, Shukla S, Fu P, Vazquez EJ, Puchowicz MA, Molter JP, et al. Synergistic simvastatin and metformin combination chemotherapy for osseous metastatic castration-resistant prostate cancer. Mol Cancer Ther. 2014; 13:2288–2302.

43. Clinicaltrials.gov. Lipitor and biGuanide to Androgen Delay Trial (LIGAND) [Internet]. Bethesda (MD): U.S. National Library of Medicine;U.S. National Institutes of Health;U.S. Department of Health and Human Services;2016. cited 2016 Mar 3. Available from: https://clinicaltrials.gov/ct2/show/study/NCT02497638?term=LIGAND&rank=8.

44. Alibhai SM, Duong-Hua M, Sutradhar R, Fleshner NE, Warde P, Cheung AM, et al. Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol. 2009; 27:3452–3458.

45. Tsai HT, Keating NL, Van Den Eeden SK, Haque R, Cassidy-Bushrow AE, Ulcickas Yood M, et al. Risk of diabetes among patients receiving primary androgen deprivation therapy for clinically localized prostate cancer. J Urol. 2015; 193:1956–1962.

46. Keating NL, Liu PH, O'Malley AJ, Freedland SJ, Smith MR. Androgen-deprivation therapy and diabetes control among diabetic men with prostate cancer. Eur Urol. 2014; 65:816–824.

47. Chen AC, Petrylak DP. Complications of androgen deprivation therapy in men with prostate cancer. Curr Oncol Rep. 2004; 6:209–215.

48. 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; 109:1495–1502.

49. Mamtani R, Pfanzelter N, Haynes K, Finkelman BS, Wang X, Keefe SM, et al. Incidence of bladder cancer in patients with type 2 diabetes treated with metformin or sulfonylureas. Diabetes Care. 2014; 37:1910–1917.

50. Zhang T, Guo P, Zhang Y, Xiong H, Yu X, Xu S, et al. The antidiabetic drug metformin inhibits the proliferation of bladder cancer cells in vitro and in vivo. Int J Mol Sci. 2013; 14:24603–24618.

51. Zhang T, Wang X, He D, Jin X, Guo P. Metformin sensitizes human bladder cancer cells to TRAIL-induced apoptosis through mTOR/S6K1-mediated downregulation of c-FLIP. Anticancer Drugs. 2014; 25:887–897.

52. Goossens ME, Buntinx F, Zeegers MP, Driessen JH, De Bruin ML, De Vries F. Influence of metformin intake on the risk of bladder cancer in type 2 diabetes patients. Br J Clin Pharmacol. 2015; 80:1464–1472.

53. Tseng CH. Metformin may reduce bladder cancer risk in Taiwanese patients with type 2 diabetes. Acta Diabetol. 2014; 51:295–303.

54. Bosetti C, Rosato V, Buniato D, Zambon A, La Vecchia C, Corrao G. Cancer risk for patients using thiazolidinediones for type 2 diabetes: a meta-analysis. Oncologist. 2013; 18:148–156.

55. He S, Tang YH, Zhao G, Yang X, Wang D, Zhang Y. Pioglitazone prescription increases risk of bladder cancer in patients with type 2 diabetes: an updated meta-analysis. Tumour Biol. 2014; 35:2095–2102.

56. Zhu Z, Shen Z, Lu Y, Zhong S, Xu C. Increased risk of bladder cancer with pioglitazone therapy in patients with diabetes: a meta-analysis. Diabetes Res Clin Pract. 2012; 98:159–163.

57. Rieken M, Xylinas E, Kluth L, Crivelli JJ, Chrystal J, Faison T, et al. Association of diabetes mellitus and metformin use with oncological outcomes of patients with non-muscle-invasive bladder cancer. BJU Int. 2013; 112:1105–1112.

58. Rieken M, Xylinas E, Kluth L, Crivelli JJ, Chrystal J, Faison T, et al. Effect of diabetes mellitus and metformin use on oncologic outcomes of patients treated with radical cystectomy for urothelial carcinoma. Urol Oncol. 2014; 32:49.e7–49.e14.

59. Nayan M, Bhindi B, Yu JL, Hermanns T, Mohammed A, Hamilton RJ, et al. The effect of metformin on cancer-specific survival outcomes in diabetic patients undergoing radical cystectomy for urothelial carcinoma of the bladder. Urol Oncol. 2015; 33:386.e7–386.e13.

60. Rieken M, Xylinas E, Kluth L, Trinh QD, Lee RK, Fajkovic H, et al. Diabetes mellitus without metformin intake is associated with worse oncologic outcomes after radical nephroureterectomy for upper tract urothelial carcinoma. Eur J Surg Oncol. 2014; 40:113–120.

61. Cheng JJ, Li H, Tan HS, Tan PH, Ng LG, Ng QS, et al. Metformin Use in Relation With Survival Outcomes of Patients With Renal Cell Carcinoma. Clin Genitourin Cancer. 2016; 14:168–175.

62. Psutka SP, Boorjian SA, Lohse CM, Stewart SB, Tollefson MK, Cheville JC, et al. The association between metformin use and oncologic outcomes among surgically treated diabetic patients with localized renal cell carcinoma. Urol Oncol. 2015; 33:67.e15–67.e23.

63. Hakimi AA, Chen L, Kim PH, Sjoberg D, Glickman L, Walker MR, et al. The impact of metformin use on recurrence and cancer-specific survival in clinically localized high-risk renal cell carcinoma. Can Urol Assoc J. 2013; 7:E687–E691.

64. Liu J, Li M, Song B, Jia C, Zhang L, Bai X, et al. Metformin inhibits renal cell carcinoma in vitro and in vivo xenograft. Urol Oncol. 2013; 31:264–270.

65. Yang FQ, Wang JJ, Yan JS, Huang JH, Li W, Che JP, et al. Metformin inhibits cell growth by upregulating microRNA-26a in renal cancer cells. Int J Clin Exp Med. 2014; 7:3289–3296.

66. Kalogirou C, Schafer D, Krebs M, Kurz F, Schneider A, Riedmiller H, et al. Metformin-derived growth inhibition in renal cell carcinoma depends on miR-21-mediated PTEN expression. Urol Int. 2016; 96:106–115.

67. Clinicaltrials.gov. The Metformin Active Surveillance Trial (MAST) Study (MAST) [Internet]. Bethesda (MD): U.S. National Library of Medicine;U.S. National Institutes of Health;U.S. Department of Health and Human Services;2016. cited 2016 Mar 6. Available from: https://clinicaltrials.gov/ct2/show/NCT01864096.