СОВРЕМЕННОЕ ПРЕДСТАВЛЕНИЕ О МОЛЕКУЛЯРНЫХ МЕХАНИЗМАХ ДЕЙСТВИЙ МЕТФОРМИНА
Обзор посвящен анализу молекулярных механизмов действия метформина, широко применяемого во всем мире, антидиабетического средства. Кроме гипогликемического действия у метформина обнаружен ряд плейотропных эффектов, в частности противоопухолевый. Эффект метформина на пролиферацию раковых клеток связан с активацией AMPK и угнетением mTOR, который играет важную роль в регуляции роста клеток. Снижение глюкозы метформином обусловлено его способностью подавлять глюконеогенез в печени через сигнальный путь от LKB1, утрата которого способствует формированию некоторых опухолей. Так как LKB1 является ключевым регулятором метаболизма глюкозы и липидов в Т-клетках, и имеет важное значение для нормального развития и функционирования Т-клеток. Существующие на сегодняшний день исследования показывают, что этот препарат оказывает свое антипролиферативное действие несколькими путями, включая прямое действие и иммунноопосредованное ингибирование опухолевого роста. Выделены два основных механизма противоопухолевого эффекта метформина: прямой (инсулиннезависимый) и непрямой (инсулинозависимый). В настоящее время механизм действия метформина на канцерогенез до конца не выяснен. Необходимы дальнейшие эксперименты и масштабные клинические исследования для выяснения клеточных и молекулярных механизмов метформина, обладающего большим потенциалом в диабетологии и онкологии.
О. Н. Уразаев 1, С. С. Искакова 1, Е. Ж. Бекмухамбетов 1,
М. Дворацка 2, Г. Дворацки 2
1 Западно-Казахстанский государственный медицинский университет
имени Марата Оспанова, г. Актобе, Казахстан;
2 Познаньский медицинский университет имени Кароля Марчинковского,
г. Познань, Польша.
Литература:
1. Дедов И. И., Бутрова С. А., Берковская М. А. Потенциальные возможности метформина в профилактике и лечении онкологических заболеваний у больных сахарным диабетом 2 типа // Ожирение и метаболизм. 2011. №1. С. 40-49.
2. Искакова С. С., Уразаев О. Н., Бекмухамбетов Е. Ж., Дворацка М., Дворацки Г. Иммуномодулирующее действие метформина при монотерапии сахарного диабета 2 типа субпопуляций Т-лимфоцитов // Сборник II Международного конгресса «Профилактика и лечение метаболических нарушений и сосудистых заболеваний. Междисциплинарный подход», Москва, 24-25 ноября, 2014. С. 47.
3. Adler A. I., Shaw E. J., Stokes T., Ruiz F. Newer agents for blood glucose control in type 2 diabetes: summary of NICE guidance // BMJ. 2009. N 338. Р. 1668.
4. Algire C., Zakikhani M., Blouin M. J., Shuai J. H., Pollak M. Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth // EndocrRelat Cancer. 2008. N 15. Р. 833-839.
5. Bailey C. J., Turner R. C. Metformin // N Engl J Med. 1996. N 334. Р. 574-579.
6. Basen-Engquist K, Chang M. Obesity and cancer risk: recent review and evidence // Curr Oncol Rep. 2011.N 13. Р. 71-76.
7. Ben Sahra, Laurent K., Loubat A., et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level // Oncogene. 2008. N.27. P.3576–3586.
8. Bodmer M., Meier C., Krähenbühl S., Jick S. S., Meier C. R. Long-term metformin use is associated with decreased risk of breast cancer // Diabetes Care. 2010.N 33(6). Р. 1304–1308.
9. Currie C. J., Poole C. D., Gale E. A. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes // Diabetologia. 2009. N 52(9). Р. 1766–1777.
10. Cusi K., Consoli A., DeFronzo R. A. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus // J ClinEndocrinolMetab. 1996. N 81. Р. 4059–4067.
11. Decensi A., et al. Metformin and cancer risk in diabetic patients: A systematic review and meta-analysis // Cancer Prev Res (Phila). 2010. N 3(11). Р. 1451–1461.
12. Diamanti-Kandarakis E., Economou F., Palimeri S., Christakou C. Metformin in polycystic ovary syndrome // Ann N Y Acad Sci.2009. N 1205. Р.192-198.
13. Dowling R. J., Zakikhani M., Fantus I. G., Pollak M., Sonenberg N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells // Cancer Res. 2007.N 67. Р. 10804-10812.
14. Dowling R. J., Goodwin P. J., Stambolic V. Understanding the benefit of metformin use in cancer treatment // BMC Med. 2011. N 9. Р. 33.
15. Eikawa S., Nishida M., Mizukami S., Yamazaki C., Nakayama E., Udono H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin // ProcNatlAcadSci U S A. 2015. N 10.112(6). Р. 1809-1814.
16. Evans J. M., Donnelly L. A., Emslie-Smith A. M., Alessi D. R., Morris A. D. Metformin and reduced risk of cancer in diabetic patients // BMJ. 2005. N330. Р. 1304–1305.
17. Foretz M., He´brard S., Leclerc J., Zarrinpashneh E., Soty M. et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/ AMPK pathway via a decrease in hepatic energy state // J Clin Invest.2010. N120. Р. 2355– 2369.
18. Frasca F., Pandini G., Sciacca L., Pezzino V., Squatrito S., Belfiore A., Vigneri R. The role of insulin receptors and IGF-I receptors in cancer and other diseases // Arch PhysiolBiochem. 2008.N 114. Р. 23-37.
19. Gallagher E. J., Le Roith D. Diabetes, cancer, and metformin: connections of metabolism and cell proliferation // Ann N Y Acad Sci. 2011. N1243. Р. 54-68.
20. Goodwin P. J., Pritchard K. I., Ennis M., Clemons M., Graham M., Fantus I. G. Insulin-lowering effects of metformin in women with early breast cancer // Clin Breast Cancer. 2008. N 8. Р. 501-505.
21. Hemkens L. G., et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues. A cohort study // Diabetologia. 2009. N 52(9). Р. 1732–1744.
22. Hosono K., Endo H., Takahashi H., Sugiyama M., Sakai E., Uchiyama T., Suzuki K., Iida H., Sakamoto Y., Yoneda K., Koide T., Tokoro C., Abe Y., Inamori M., Nakagama H., Nakajima A. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial // Cancer Prev Res (Phila). 2010.N 3. Р. 1077-1083.
23. Hundal R. S., Krssak M., Dufour S., Laurent D., Lebon V., Chandramouli V., Inzucchi S. E., Schumann W. C., Petersen K. F., Landau B. R., Shulman G. I. Mechanism by which metformin reduces glucose production in type 2 diabetes // Diabetes. 2000. N 49. P. 2063–2069.
24. Inoki K., Zhu T., Guan K. L. TSC2 mediates cellular energy response to control cell growth and survival // Cell 2003. N 115. P. 577-590.
25. Jalving M., Gietema J. A., Lefrandt J. D., de Jong S., Reyners A. K., Gans R. O., de Vries E. G. Metformin: taking away the candy for cancer? // Eur J Cancer. 2010. N 46. P. 2369–2380.
26. Kirpichnikov D., McFarlane S. I., Sowers J. R. Metformin: an update // Ann Intern Med. N 137 (1). 2002. Р. 25–33.
27. LandmanG. W., Kleefstra N., van Hateren K. J., Groenier K. H., Gans R. O., Bilo H. J. Metformin associated withlowercancermortality in type 2 diabetes: ZODIAC-16 // Diabetes Care. 2010. N 33(2). Р. 322—326.
28. Lee J. W., Soung Y. H., Kim S. Y., Lee H. W., Park W. S., Nam S. W., Kim S. H., Lee J. Y., Yoo N. J., Lee S. H. PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas // Oncogene. 2005. N 24. P. 1477-1480.
29. Libby G., et al. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes // Diabetes Care. 2009. N 32(9). P. 1620–1625.
30. MacIver N. J., Blagih J., Saucillo D. C., Tonelli L., Griss T., et al. The Liver Kinase B1 Is a Central Regulator of T Cell Development, Activation, and Metabolism // The Journal of Immunology. 2011. N 187. P. 4187–4198.
31. Markman B., Atzori F., Perez-Garcia J., Tabernero J., Baselga J. Status of PI3K inhibition and biomarker development in cancer therapeutics // Ann Oncol. 2010.N 21. P. 683-691.
32. McFarland M. S., Cripps R. Diabetes mellitus and increased risk of cancer: focus on metformin and the insulin analogs // Pharmacotherapy.2010. N 30(11). P. 1159–1178.
33. Natali A., Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review // Diabetologia. 2006. N 49 P. 434-441.
34. Nathan D. M., Buse J. B., Davidson M. B., Ferrannini E., Holman R. R., Sherwin R., Zinman B. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes // Diabetes Care. 2009. N 32. P. 193–203.
35. Niraula S., Stambolic V., Dowling R. J., Ennis M., Chang M. C., Done S. J., Hallak S., Hood N., Goodwin P. J. Clinical and biologic effects of metformin in early stage breast cancer // Cancer Res. 2010. N 70(24). 104s. Abs No. P. 03-06.
36. Noto H., Goto A., Tsujimoto T., Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis // PLoS ONE. 2012. N7(3). P. 33411.
37. Oakhill J. S., Steel R., Chen Z. P., Scott J. W., Ling N., Tam S., Kemp B. E. AMPK is a direct adenylatecharge-regulated protein kinase // Science. 2011. N 332. P. 1433–1435.
38. Oliveria S. A, Koro C. E., Yood M. U., Sowell M. Cancer incidence among patients treated with antidiabetic pharmacotherapy // Diabetes. Metabol. Syndrome. Clin. Res. Reviews. 2008. N 2. Р. 47-57.
39. Pearce E. L., et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism // Nature.2009. N 60(7251). P. 103–107.
40. Rotella C. M., Monami M., Mannucci E. Metformin beyond diabetes: new life for an old drug // Curr Diabetes Rev. 2006. N 2. P. 307-315.
41. Shackelford D. B., Shaw R. J. The LKB1-AMPK pathway: metabolism and growth control in tumor suppression // Nat. Rev. Cancer. 2009. N 8. P. 563-575.
42. Shaw R. J., et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin // Science. 2005. N 310(5754). P. 1642–1646.
43. Shikata K., Ninomiya T., Kiyohara Y. Diabetes mellitus and cancer risk: review of the epidemiological evidence // Cancer Sci. 2013. N 104(1). P. 9-14.
44. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group // Lancet. 1998. N 352. P. 854-865.
45. Viollet B., Guigas B., Leclerc J., Hebrard S., Lantier L., Mounier R., Andreelli F., Foretz M. AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives // ActaPhysiol (Oxf). 2009. N. 196. P. 81–98.
46. Viollet B., Guigas B., SanzGarcia N., Leclerc J., Foretz M., Andreelli F. Cellular and molecular mechanisms of metformin: an overview // ClinSci (Lond). 2012. N 122(6). P. 253-70.
47. Wang Z., Lai S. T., Xie L., Zhao J. D., Ma N. Y., Zhu J., Ren Z. G., Jiang G.L. Metformin is associated with reduced risk of pancreatic cancerin patients with type 2 diabetesmellitus: asystematicreviewandmeta-analysis // Diabetes Res ClinPract. 2014. N 106(1). P. 19-26.
48. Xiao B., Sanders M. J., Underwood E., Heath R., Mayer F. V., Carmena D., Jing C., Walker P. A., Eccleston J. F., Haire L. F., Saiu P., Howell S. A., Aasland R., Martin S. R., Carling D., Gamblin S. J. Structure of mammalian AMPK and its regulation by ADP // Nature. 2011. N 472. P. 230-233.
49. Xu C. X., Zhu H. H., Zhu Y. M. Diabetes and cancer: Associations, mechanisms, and implications for medical practice // World J Diabetes. 2014. N 15. 5(3). P. 372-380.
50. Zakikhani M., Dowling R., Fantus I. G., Sonenberg N., Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells // Cancer Res. 2006.N 66. P. 10269-10273.
51. Zarrouk M., Finlay D. K., Foretz M., Viollet B., Cantrell D. A. Adenosine-mono-phosphate-activated protein kinase independent effects of metformin in T cells // PLoS One. 2014. N 2;9(9). P. 106710.
52. Zhou G., Myers R., Li Y., Chen Y., Shen X., Fenyk-Melody J., Wu M., Ventre J., Doebber T., Fujii N., Musi N., Hirshman M. F., Goodyear L. J., Moller D. E. Role of AMP-activated protein kinase in mechanism of metformin action // J Clin Invest. 2001. N 108. P. 1167-1174.
53. Zhou G. R., Myers, Li Y. et al. Role of AMP-activated protein kinase in mechanism of metformin action // J. Clin. Invest. 2001. N 8. Р. 1167-1174.
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8. Bodmer M., Meier C., Krähenbühl S., Jick S. S., Meier C. R. Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care. 2010. N 33(6). Р. 1304-1308.
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17. Foretz M., He´brard S., Leclerc J., Zarrinpashneh E., Soty M. et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/ AMPK pathway via a decrease in hepatic energy state. J Clin Invest.2010. N120. Р. 2355– 2369.
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20. Goodwin P. J., Pritchard K. I., Ennis M., Clemons M., Graham M., Fantus I. G. Insulin-lowering effects of metformin in women with early breast cancer. Clin Breast Cancer. 2008. N 8. Р. 501-505.
21. Hemkens L. G., et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues. A cohort study. Diabetologia. 2009. N 52(9). Р. 1732–1744.
22. Hosono K., Endo H., Takahashi H., Sugiyama M., Sakai E., Uchiyama T., Suzuki K., Iida H., Sakamoto Y., Yoneda K., Koide T., Tokoro C., Abe Y., Inamori M., Nakagama H., Nakajima A. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial // Cancer Prev Res (Phila). 2010. N 3. Р. 1077-1083.
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24. Inoki K., Zhu T., Guan K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003. N 115. P. 577-590.
25. Jalving M., Gietema J. A., Lefrandt J. D., de Jong S., Reyners A. K., Gans R. O., de Vries E. G. Metformin: taking away the candy for cancer? Eur J Cancer. 2010. N 46. P. 2369–2380.
26. Kirpichnikov D., McFarlane S. I., Sowers J. R. Metformin: an update. Ann Intern Med. N 137 (1). 2002. Р. 25–33.
27. LandmanG. W., Kleefstra N., van Hateren K. J., Groenier K. H., Gans R. O., Bilo H. J. Metformin associated withlowercancermortality in type 2 diabetes: ZODIAC-16. Diabetes Care. 2010. N 33(2). Р. 322—326.
28. Lee J. W., Soung Y. H., Kim S. Y., Lee H. W., Park W. S., Nam S. W., Kim S. H., Lee J. Y., Yoo N. J., Lee S. H. PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene. 2005. N 24. P. 1477-1480.
29. Libby G., et al. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009. N 32(9). P. 1620–1625.
30. MacIver N. J., Blagih J., Saucillo D. C., Tonelli L., Griss T., et al. The Liver Kinase B1 Is a Central Regulator of T Cell Development, Activation, and Metabolism. The Journal of Immunology. 2011. N 187. P. 4187–4198.
31. Markman B., Atzori F., Perez-Garcia J., Tabernero J., Baselga J. Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann Oncol. 2010.N 21. P. 683-691.
32. McFarland M. S., Cripps R. Diabetes mellitus and increased risk of cancer: focus on metformin and the insulin analogs. Pharmacotherapy.2010. N 30(11). P. 1159–1178.
33. Natali A., Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia. 2006. N 49 P. 434-441.
34. Nathan D. M., Buse J. B., Davidson M. B., Ferrannini E., Holman R. R., Sherwin R., Zinman B. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009. N 32. P. 193–203.
35. Niraula S., Stambolic V., Dowling R. J., Ennis M., Chang M. C., Done S. J., Hallak S., Hood N., Goodwin P. J. Clinical and biologic effects of metformin in early stage breast cancer. Cancer Res. 2010. N 70(24). 104s. Abs No. P. 03-06.
36. Noto H., Goto A., Tsujimoto T., Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS ONE. 2012. N7(3). P. 33411.
37. Oakhill J. S., Steel R., Chen Z. P., Scott J. W., Ling N., Tam S., Kemp B. E. AMPK is a direct adenylatecharge-regulated protein kinase. Science. 2011. N 332. P. 1433–1435.
38. Oliveria S. A, Koro C. E., Yood M. U., Sowell M. Cancer incidence among patients treated with antidiabetic pharmacotherapy. Diabetes. Metabol. Syndrome. Clin. Res. Reviews. 2008. N 2. Р. 47-57.
39. Pearce E. L., et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature.2009. N 60(7251). P. 103–107.
40. Rotella C. M., Monami M., Mannucci E. Metformin beyond diabetes: new life for an old drug. Curr Diabetes Rev. 2006. N 2. P. 307-315.
41. Shackelford D. B., Shaw R. J. The LKB1-AMPK pathway: metabolism and growth control in tumor suppression. Nat. Rev. Cancer. 2009. N 8. P. 563-575.
42. Shaw R. J., et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005. N 310(5754). P. 1642–1646.
43. Shikata K., Ninomiya T., Kiyohara Y. Diabetes mellitus and cancer risk: review of the epidemiological evidence. Cancer Sci. 2013. N 104(1). P. 9-14.
44. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998. N 352. P. 854-865.
45. Viollet B., Guigas B., Leclerc J., Hebrard S., Lantier L., Mounier R., Andreelli F., Foretz M. AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. ActaPhysiol (Oxf). 2009. N. 196. P. 81–98.
46. Viollet B., Guigas B., SanzGarcia N., Leclerc J., Foretz M., Andreelli F. Cellular and molecular mechanisms of metformin: an overview. ClinSci (Lond). 2012. N 122(6). P. 253-70.
47. Wang Z., Lai S. T., Xie L., Zhao J. D., Ma N. Y., Zhu J., Ren Z. G., Jiang G.L. Metformin is associated with reduced risk of pancreatic cancerin patients with type 2 diabetesmellitus: asystematicreviewandmeta-analysis. Diabetes Res ClinPract. 2014. N 106(1). P. 19-26.
48. Xiao B., Sanders M. J., Underwood E., Heath R., Mayer F. V., Carmena D., Jing C., Walker P. A., Eccleston J. F., Haire L. F., Saiu P., Howell S. A., Aasland R., Martin S. R., Carling D., Gamblin S. J. Structure of mammalian AMPK and its regulation by ADP. Nature. 2011. N 472. P. 230-233.
49. Xu C. X., Zhu H. H., Zhu Y. M. Diabetes and cancer: Associations, mechanisms, and implications for medical practice. World J Diabetes. 2014. N 15. 5(3). P. 372-380.
50. Zakikhani M., Dowling R., Fantus I. G., Sonenberg N., Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 2006.N 66. P. 10269-10273.
51. Zarrouk M., Finlay D. K., Foretz M., Viollet B., Cantrell D. A. Adenosine-mono-phosphate-activated protein kinase independent effects of metformin in T cells. PLoS One. 2014. N 2;9(9). P. 106710.
52. Zhou G., Myers R., Li Y., Chen Y., Shen X., Fenyk-Melody J., Wu M., Ventre J., Doebber T., Fujii N., Musi N., Hirshman M. F., Goodyear L. J., Moller D. E. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001. N 108. P. 1167-1174.
53. Zhou G. R., Myers, Li Y. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 2001. N 8. Р. 1167-1174.