Metformin, Diyabet ve Meme Kanseri Üçgeni

Yıl 2020, Cilt: 3 Sayı: 2, 55 - 65, 01.07.2020

Güven Yenmiş

Öz

Metformin, tip 2 diyabet (T2D) tedavisinde kullanılan umut verici, iyi bilinen bir klinik
ilaçtır. Gerçekleştirilen epidemiyolojik çalışmaların meta-analizlerine göre, T2D’nin kanser
gelişimiyle-özellikle meme kanserinde-insidans açısından-negatif bir korelasyonu vardır ve
kanser hastaları metformin ile tedavi edildiğinde mortalite riskinin azaldığının gösterilmesi,
metformin ve tümör oluşumu arasında bir bağlantı olduğunu düşündürmekte bu durumda birçok
araştırmacının dikkatini çekmektedir. İlginçtir ki, sadece in vivo değil, aynı zamanda in vitro
çalışmalar da metforminin direkt bir antitümör etkisine sahip olduğunu doğrulamaktadır, çünkü
metformin, tümör proliferasyonunu baskılayabilir ve hücre döngüsü durmasını, apoptozunu
ve hatta tümör hücrelerinin otofajisini tetikleyebilir. Bununla birlikte, metforminin kanser
hücreleri üzerinde inhibe edici etkisini ortaya çıkaran kesin mekanizma henüz tam olarak
belirlenmemiştir. Bu derlemede, metforminin etki mekanizması, hem T2D, hem de kanser ile
ilişkili olarak değerlendirilmiştir. Kanser düzenleme yollarının detaylandırılması, metformini
kanser tedavisinde yeni yaklaşımlar için bir aday olarak göstermektedir. Bu nedenle, metformin
tedavisinin kanser önleme ve nüks durumunda hem tekli hem de adjuvan tedavilerde doğru
etkinliğini doğrulamak için ek araştırmalara ihtiyaç vardır. Yapılacak büyük ölçekli klinik
araştırmalar metforminin anti-kanser etkisini desteklerse, metformin, kanser tedavisi için umut
vadeden, yeniden konumlandırılmış bir seçenek haline gelebilir.

Anahtar Kelimeler

Metformin,, Meme kanseri,, Tip 2 diyabet,, Kanser ilacı

The Triangle of Metformin, Type 2 diabetes mellitus, and the Breast Cancer

Öz

Metformin is a promising well-known clinical drug used in type 2 diabetes mellitus (T2DM)
treatment. According to meta-analyses of epidemiological studies, T2DM has a negative
correlation-in case of incidence- with cancer development-especially breast cancer- and that
patients with cancer have decreased risk of mortality if treated with metformin, suggesting a
linkage between metformin and tumorigenesis which draws the attention of many researchers.
Interestingly enough, not only in vivo but also in vitro studies have confirmed that metformin
has a straightforward antitumor effect, as it may suppress tumor proliferation and trigger cell
cycle arrest, apoptosis, and even autophagy of tumor cells. However, the exact mechanism by
which metformin produces its inhibitory effect on cancer cells has not been well established yet.
Here in this review, the mechanism of action of metformin is evaluated in correlation with
both T2DM and cancer. Well-established cancer regulation pathways nominate metformin as
a candidate for novel approaches in cancer treatment. Thus, additional research is needed to
confirm the correct efficacy of metformin therapy in both single or adjuvant therapies in case of cancer prevention and recurrence. If large-scale clinical trials support the anti-cancer effect of metformin,
metformin could become a rewarding and repositioned option for cancer therapy.

Anahtar Kelimeler

Metformin, Breast cancer, Type 2 Diabetes Mellitus, Cancer treatment drug

Kaynakça

• 1. Howlett HCS, Bailey CJ. Galegine and antidiabetic plants. In: Bailey CJ, Campbell IW, Chan JCN, Davidson JA, Howlett HCS, Ritz P (eds) Metformin—the gold standard. Wiley, Chichester; 2007, pp 3–9.
• 2. Muller H, Reinwein H. Zur pharmakologie des Galegins. Arch Exp Pathol Pharmakol 1927; 125: 212–228.
• 3. Viollet B, Guigas B, Sanz Garcia N, et al. Cellular and molecular mechanisms of metformin: an overview. Clin. Sci. (Lond.) 2012; 122, 253–270.
• 4. Pryor, R.; Cabreiro, F. Repurposing metformin: An old drug with new tricks in its binding pockets. Biochem. J. 2015; 471, 307–322.
• 5. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycae¬mia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012; 55(6): 1577–1596.
• 6. Polskie Towarzystwo Diabetologiczne. Zalecenia kliniczne dotyczące postępowania z chorym na cukrzycę 2016. Diabetol Klin. 2016; 2(supl. A).
• 7. Segal ED, Yasmeen A, Beauchamp MC, et al. Relevance of the OCT1 transporter to the antineoplastic effect of biguanides. Biochem. Biophys. Res. Commun. 2011; 414, 694–699.
• 8. Sogame Y, Kitamura A, Yabuki M, et al. Transport of biguanides by human organic cation transporter OCT2. Biomed. Pharmacother. 2013; 67, 425–430.
• 9. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 2000. 348, 607–614.
• 10. Brown JB, Pedula K, Barzilay J, et al. Lactic acidosis rates in type 2 diabetes. Diabetes Care 1998, 1659–1663.
• 11. Jin HE, Hong SS, Choi MK, et al. Reduced antidiabetic effect of metformin and downregulation of hepatic Oct1 in rats with ethynylestradiolinduced cholestasis. Pharm. Res. 2009; 26, 549–559.
• 12. Wilcock C, and Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 1994; 24, 49–57.
• 13. Zhou G, Myers R, Li Y, et al. Role of AMPactivated protein kinase in mechanism of metformin action. J. Clin. Invest. 2001; 108, 1167–1174.
• 14. Shaw RJ, Lamia KA, Vasquez D, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005; 310, 1642–1646.
• 15. He L, Sabet A, Djedjos S, et al. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 2009; 137, 635–646.
• 16. El-Mir MY, Nogueira V, Fontaine E, et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 2000; 275, 223–228.
• 17. Stephenne X, Foretz M, Taleux N, et al. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia 2011; 54, 3101–3110.
• 18. Detaille D, Guigas B, Chauvin C, et al. Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes 2005; 54, 2179–2187.
• 19. El-Mir MY, Detaille D, R-Villanueva et al. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J. Mol. Neurosci 2008. 34, 77–87.
• 20. Bridges HR, Jones AJ, Pollak MN, Hirst J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem. J. 2014; 462, 475–487.
• 21. Wheaton WW, Weinberg SE, Hamanaka RB, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife 2014; 3, e02242.
• 22. Correia S, Carvalho C, Santos MS, et al. Mechanisms of action of metformin in type 2 diabetes and associated complications: An overview. Mini Rev. Med. Chem. 2008; 8, 1343–1354.
• 23. Samuel SM, Varghese E, Varghese S, Busselberg D. Challenges and perspectives in the treatment of diabetes associated breast cancer. Cancer Treat. Rev. 2018, 70, 98–111.
• 24. Nesti L, Natali A. Metformine ects on the heart and the cardiovascular system: A review of experimental and clinical data. Nutr. Metab. Cardiovasc. Dis. 2017; 27, 657–669.
• 25. Iranshahy M, Rezaee R, Karimi G. Hepatoprotective activity of metformin: A new mission for an old drug? Eur. J. Pharmacol. 2019;850,1–7.
• 26. Li Y, Liu L, Wang B, et al. Metformin in nonalcoholic fatty liver disease: A systematic review and meta-analysis. Biomed. Rep. 2013; 1, 57–64.
• 27. Yanardag R, Ozsoy-Sacan O, Bolkent S, et al. Protective effects of metformin treatment on the liver injury of streptozotocin-diabetic rats. Hum. Exp. Toxicol. 2005;24,129–135.
• 28. Brackett CC. Clarifying metformin’s role and risks in liver dysfunction. J. Am. Pharm. Assoc. 2010;50,407–410.
• 29. Corremans R, Vervaet BA, D’Haese PC, et al. Metformin: A Candidate Drug for Renal Diseases. Int. J. Mol. Sci. 2018; 20, 42.
• 30. Rotermund C, Machetanz G, Fitzgerald JC. The Therapeutic Potential of Metformin in Neurodegenerative Diseases. Front. Endocrinol. 2018; 9, 400.
• 31. Ma J, Liu J, Yu H, et al. Beneficial Effect of Metformin on Nerve Regeneration and Functional Recovery After Sciatic Nerve Crush Injury in Diabetic Rats. Neurochem. Res. 2016; 41, 1130–1137.
• 32. Mao-Ying QL, Kavelaars A, Krukowski K, et al. The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model. PLoS ONE 2014; 9, e100701.
• 33. Bahrambeigi S, Yousefi B, Rahimi M, Shafiei- Irannejad, V. Metformin; an old antidiabetic drug with new potentials in bone disorders. Biomed. Pharmacother. 2019; 109, 1593–1601.
• 34. Prattichizzo F, Giuliani A, Mensà E, et al. Pleiotropic effects of metformin: Shaping the microbiome to manage type 2 diabetes and postpone ageing. Ageing Res. Rev. 2018, 48, 87–98.
• 35. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a Tool to Target Aging. Cell Metab. 2016;23,1060–1065.
• 36. Novelle MG, Ali A, Dieguez C, et al. Metformin: A Hopeful Promise in Aging Research. Cold Spring Harb. Perspect. Med. 2016; 6, a025932.
• 37. DeCensi A, Puntoni M, Goodwin P, et al. Metformin and Cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res. 2010;3:1451–61.
• 38. Zhang ZJ, Zheng ZJ, Kan H, et al, Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis, Diabetes Care 2011;34,2323–2328.
• 39. Zhang ZJ, Zheng ZJ, Shi R, et al. Kip, Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis, J. Clin. Endocrinol. Metab. 2012; 97, 2347–2353.
• 40. Zhang ZJ, Bi Y, Li S, et al. Reduced risk of lung cancer with metformin therapy in diabetic patients: a systematic review and metaanalysis, Am. J. Epidemiol. 2014;180, 11–14.
• 41. Zhang ZJ, Li S, The prognostic value of metformin for cancer patients with concurrent diabetes: a systematic review and metaanalysis, Diabetes Obes. Metab. 2014;16,707– 710.
• 42. Boyle P, Boniol M, Koechlin A, et al. Diabetes and breast cancer risk: Ameta-analysis. Br. J. Cancer 2012; 107, 1608–1617.
• 43. Hardefeldt PJ, Edirimanne S, Eslick GD. Diabetes increases the risk of breast cancer: A meta-analysis. Endocr. Relat. Cancer 2012;19,793–803.
• 44. Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: A metaanalysis. Int. J. Cancer 2007;121,856–862.
• 45. StattinP, Björ O, Ferrari P, et al. Prospective Study of Hyperglycemia and Cancer Risk. Diabetes Care 2007; 30, 561.
• 46. Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: A consensus report. Diabetes Care 2010;33,1674–1685.
• 47. Farmer RE, Ford D, Forbes HJ, et al., Metformin and cancer in type 2 diabetes: a systematic review and comprehensive bias evaluation, Int. J. Epidemiol. 2017;46,728–744.
• 48. Brem RF . Radiofrequency Ablation of Breast Cancer: A Step Forward . Radiological Society of North America; 2018 .
• 49. Warburg O . On the origin of cancer cells. Science .1956;123:309–314.
• 50. Phan LM , Yeung S-CJ , Lee M-H. Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol Med . 2014;11:1.
• 51. Camacho L, Dasgupta A, Jiralerspong S. Metformin in breast cancer-an evolving mystery . BioMed Central; 2015.
• 52. Dowling RJ, Niraula S, Chang MC, et al. Changes ininsulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res 2015;17:32.
• 53. Zakikhani M, Dowling R, Fantus IG, et al. Metformin is an AMP kinase–dependent growth in- hibitor for breast cancer cells. Cancer Res 2006;66:10269–10273.
• 54. Kleinberg DL, Wood TL, Furth PA, Lee AV. Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions, Endocr. Rev. 2009;30,51–74.
• 55. Husing A, Fortner RT, Kuhn T, et al, Added value of serum hormone measurements in risk prediction models for breast cancer for women not using exogenous hormones: results from the EPIC cohort, Clin. Cancer Res. 2017;23,4181– 4189.
• 56. Martin-Castillo B, Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. Metformin and cancer: doses, mechanisms and the dandelion and hormetic phenomena. Cell Cycle 2010;9:1057–1064.
• 57. Gershell L. Type 2 Diabetes Market. Nature Publishing Group; 2005.
• 58. Werner EA, Bell J. CCXIV. The preparation of methylguanidine, and of ββ-dimethylguanidine by the interac- tion of dicyanodiamide, and methylammonium and dimethylammonium chlorides respectively. J Chem Soc Trans. 1922;121:1790–1794.
• 59. Galluzzi L, Kepp O, Vander Heiden MG, Kroemer G. Metabolic targets for cancer therapy. Nat Rev Drug Discovery 2013;12:829.
• 60. Evans JMM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005;330:1304–5.
• 61. Saini N, Yang X. Metformin as an anti-cancer agent: actions and mechanisms targeting cancer stem cells. Acta Biochim Biophys Sin Shanghai. 2018;50:133–43.
• 62. Tang GH, Satkunam M, Pond GR, et al. Association of metformin with breast cancer incidence and mortality in patients with type 2 diabetes: a GRADE assessed systematic review and meta-analysis. Cancer Epidemiol Biomark Prev. 2018;27:627–35.
• 63. Wysocki PJ, Wierusz-Wysocka B. Obesity, hyperinsulinemia and breast cancer: novel targets and a novel role for metformin. Expert Rev Mol Diagn. 2010;10:509–19.
• 64. Pulito C, Donzelli S, Muti P, et al. microRNAs and cancer metabolism reprogramming: the paradigm of metformin. Ann Transl Med. 2014;2:58.
• 65. ChenW, Wang S, Tian T, et al. Phenotypes and genotypes of insulin-like growth factor 1, IGF-binding protein-3 and cancer risk: evidence from 96 studies. Eur J Hum Genet. 2009;17:1668–75.
• 66. Weinberg SE, Chandel NS. Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol. 2015;11:9–15.
• 67. El-Haggar SM, El-Shitany NA, Mostafa MF, El-Bassiouny NA. Metformin may protect nondiabetic breast cancer women from metastasis. Clin Exp Metastasis. 2016;33:339– 57.
• 68. Liu B, Fan Z, Edgerton SM, et al. Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of erbB2/IGF-1 receptor interactions. Cell Cycle 2011;10:2959–66.
• 69. Hatoum D, McGowan EM. Recent advances in the use of metformin: can treating diabetes prevent breast cancer? Biomed Res Int 2015;2015:1–13.
• 70. Pizzuti L, Vici P, Di Lauro L, et al. Metformin and breast cancer: basic knowledge in clinical context. Cancer Treat Rev Elsevier Ltd. 2015;41:441–7.
• 71. Li P, Zhao M, Parris AB, Feng X, Yang X. P53 is required for metformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. Biochem Biophys Res Commun Elsevier Ltd. 2015;464:1267–74.
• 72. Queiroz EAIF, Puukila S, Eichler R, et al. Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF-7 breast cancer cells. PLoS One 2014;9.
• 73. Hu T, Chung YM, Guan M, et al. Reprogramming ovarian and breast cancer cells into noncancerous cells by low-dose metformin or SN-38 through FOXO3 activation. Sci Rep. 2014;4:1–13.
• 74. Davila D, Connolly NMC, Bonner H, et al. Two-step activation of FOXO3 by AMPK generates a coherent feed-forward loop determining excitotoxic cell fate. Cell Death Differ. 2012;19:1677–88.
• 75. Wahdan-Alaswad RS, Cochrane DR, Spoelstra NS, et al. Metformin-induced killing of triplenegative breast cancer cells is mediated by reduction in fatty acid synthase via miRNA- 193b. Horm Cancer NIH Public Access 2014;5:374–89.
• 76. Yang J, Wei J, Wu Y, et al. Metformin induces ER stress-dependent apoptosis through miR- 708-5p/ NNAT pathway in prostate cancer. Oncogenesis 2015;4:e158–8.
• 77. Li W, Yuan Y, Huang L, Qiao M, Zhang Y. Metformin alters the expression profiles of microRNAs in human pancreatic cancer cells. Diabetes Res Clin Pract 2012;96:187–95.
• 78. Cufí S, Vazquez-Martin A, Oliveras-Ferraros C, et al. Metformin lowers the threshold for stress-induced senescence: a role for the microRNA-200 family and miR-205. Cell Cycle 2012;11:1235–46.
• 79. Zhang J, Li G, Chen Y, et al. Metformin inhibits tumorigenesis and tumor growth of breast cancer cells by upregulating miR-200c but downregulating AKT2 expression. J Cancer 2017;8:1849–64.
• 80. Zhao W, Zhang X, Liu J, et al. miR-27amediated antiproliferative effects of metformin on the breast cancer cell line MCF-7. Oncol Rep 2016;36:3691–9.