Old Drug, New Tricks: Metformin in Treatment of Patients with Type 2 Diabetes Mellitus Complicated with Liver Cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 QUANSheng-wei , PANGXin-ya ,  GAOFeng

Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China;

Corresponding author：

GAOFeng, Email: 2601693448@qq.com

Keywords：

Metformin; Type 2 diabetes mellitus; Liver cancer; Pathogenesis; Treatment

DOI：

10.7507/1007-9424.20150167

Video：

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Objective To understand the role of metformin on reducing incidence of type 2 diabetes mellitus (T2MD) patients complicated with liver cancer. Method The related literatures of metformin treated patients with T2MD complicated with liver cancer at home and abroad in recent years were reviewed. Results A large number of epidemiological and clinical data showed that the metformin might prevent the occurrence of the T2MD patients complicated with liver cancer, its mechanism was mainly inhibited the proliferation of hepatoma cells through the ATM-LKB1-AMPK-mTOR pathway, PI3K/Akt/mTOR pathway, or miRNA. The current controversy was the authenticity of the data, the influencing factors included the aging problem and characteristics of metformin user. The prospective study design rigorous remained to be clarified. Conclusion Metformin could reduce the incidence of T2MD patients complicated with liver cancer, and could inhibit the growth of liver cancer cells, which provides a new way of thinking for the comprehensive treatment of liver cancer.

Citation： QUANSheng-wei, PANGXin-ya, GAOFeng. Old Drug, New Tricks: Metformin in Treatment of Patients with Type 2 Diabetes Mellitus Complicated with Liver Cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2015, 22(5): 642-645. doi: 10.7507/1007-9424.20150167 Copy

1.	Zheng YW, Li RM, Zhang XW, et al. Current adoptive immunotherapy in non-small cell lung cancer and potential influence of therapy outcome. Cancer Invest, 2013, 31(3):197-205.
2.	Nathan DM, Buse JB, Davidson MB, et al. 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, 32(1):193-203.
3.	Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008:GLOBOCAN 2008. Int J Cancer, 2010, 127(12):2893-2917.
4.	王永川, 魏丽娟, 刘俊田, 等.发达与发展中国家癌症发病率与死亡率的比较与分析.中国肿瘤临床, 2012, 39(10):679-682.
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6.	徐瑜, 毕宇芳, 王卫庆, 等.中国成人糖尿病流行与控制现状-2010年中国慢病监测暨糖尿病专题调查报告解读.中华内分泌代谢杂志, 2014, 30(3):184-187.
7.	Lee MS, Hsu CC, Wahlqvist ML, et al. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese:a representative population prospective cohort study of 800 000 individuals. BMC Cancer, 2011, 11:20.
8.	高姗, 杨万水, 高静, 等.糖尿病与原发性肝癌队列研究的Meta分析.中华预防医学杂志, 2010, 44(8):711-716.
9.	Yuan JM, Govindarajan S, Arakawa K, et al. Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in Blacks and Whites in the U.S. Cancer, 2004, 101(5):1009-1017.
10.	Liu B, Fan Z, Edgerton SM, et al. Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle, 2009, 8(13):2031-2040.
11.	Rattan R, Giri S, Hartmann LC, et al. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med, 2011, 15(1):166-178.
12.	Tan BK, Adya R, Chen J, et al. Metformin treatment exerts antiinvasive and antimetastatic effects in human endometrial carcinoma cells. J Clin Endocrinol Metab, 2011, 96(3):808-816.
13.	Kisfalvi K, Eibl G, Sinnett-Smith J, et al. Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res, 2009, 69(16):6539-6545.
14.	Zhang ZJ, Zheng ZJ, Kan H, et al. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes:a metaanalysis. Diabetes Care, 2011, 34(10):2323-2328.
15.	Memmott RM, Mercado JR, Maier CR, et al. Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev Res (Phila), 2010, 3(9):1066-1076.
16.	Jung JW, Park SB, Lee SJ, et al. Metformin represses self-renewal of the human breast carcinoma stem cells via inhibition of estrogen receptor-mediated OCT4 expression. PLoS One, 2011, 6(11):e28068.
17.	Zhang H, Gao C, Fang L, et al. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients:a meta-analysis. Scand J Gastroenterol, 2013, 48(1):78-87.
18.	Currie CJ, Poole CD, Jenkins-Jones S, et al. Mortality after incident cancer in people with and without type 2 diabetes:impact of metformin on survival. Diabetes Care, 2012, 35(2):299-304.
19.	Wang P, Kang D, Cao W, et al. Diabetes mellitus and risk of hepatocellular carcinoma:a systematic review and meta-analysis. Diabetes Metab Res Rev, 2012, 28(2):109-122.
20.	Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, et al. Metformin activates an ataxia telangiectasia mutated (ATM)/Chk2-regulated DNA damage-like response. Cell Cycle, 2011, 10(9):1499-1501.
21.	Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem, 2008, 114(1):63-70.
22.	Zhou Q, Lui VW, Yeo W. Targeting the PI3K/Akt/mTOR pathway in hepatocellular carcinoma. Future Oncol, 2011, 7(10):1149-1167.
23.	Bhalla K, Hwang BJ, Dewi RE, et al. Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis. Cancer Prev Res (Phila), 2012, 5(4):544-552.
24.	Dowling RJ, Zakikhani M, Fantus IG, et al. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res, 2007, 67(22):10804-10812.
25.	Lee CH, Subramanian S, Beck AH, et al. MicroRNA profiling of BRCA1/2 mutation-carrying and non-mutation-carrying highgrade serous carcinomas of ovary. PLoS One, 2009, 4(10):e7314.
26.	Loubière C, Dirat B, Tanti JF, et al. New perspectives for metformin in cancer therapy. Ann Endocrinol (Paris), 2013, 74(2):130-136.
27.	Landman GW, Kleefstra N, Van Hateren KJ, et al. Metformin associated with lower cancer mortality in type 2 diabetes:ZODIAC-16. Diabetes Care, 2010, 33(2):322-326.
28.	Peter ME. Let-7 and miR-200 microRNAs:guardians against pluripotency and cancer progression. Cell Cycle, 2009, 8(6):843-852.
29.	Rattan R, Graham RP, Maguire JL, et al. Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia, 2011, 13(5):483-491.
30.	Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer:a consensus report. Diabetes Care, 2010, 33(7):1674-1685.

1. Zheng YW, Li RM, Zhang XW, et al. Current adoptive immunotherapy in non-small cell lung cancer and potential influence of therapy outcome. Cancer Invest, 2013, 31(3):197-205.
2. Nathan DM, Buse JB, Davidson MB, et al. 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, 32(1):193-203.
3. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008:GLOBOCAN 2008. Int J Cancer, 2010, 127(12):2893-2917.
4. 王永川, 魏丽娟, 刘俊田, 等.发达与发展中国家癌症发病率与死亡率的比较与分析.中国肿瘤临床, 2012, 39(10):679-682.
5. International Diabetes Federation. Diabetes Atlas:Sixth edition. Brussels:International Diabetes Federation, 2013. http://www.idf.org/sites/default/files/EN-6E-Atlas-Full-0.pdf. Accessed December 8, 2013.
6. 徐瑜, 毕宇芳, 王卫庆, 等.中国成人糖尿病流行与控制现状-2010年中国慢病监测暨糖尿病专题调查报告解读.中华内分泌代谢杂志, 2014, 30(3):184-187.
7. Lee MS, Hsu CC, Wahlqvist ML, et al. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese:a representative population prospective cohort study of 800 000 individuals. BMC Cancer, 2011, 11:20.
8. 高姗, 杨万水, 高静, 等.糖尿病与原发性肝癌队列研究的Meta分析.中华预防医学杂志, 2010, 44(8):711-716.
9. Yuan JM, Govindarajan S, Arakawa K, et al. Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in Blacks and Whites in the U.S. Cancer, 2004, 101(5):1009-1017.
10. Liu B, Fan Z, Edgerton SM, et al. Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle, 2009, 8(13):2031-2040.
11. Rattan R, Giri S, Hartmann LC, et al. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med, 2011, 15(1):166-178.
12. Tan BK, Adya R, Chen J, et al. Metformin treatment exerts antiinvasive and antimetastatic effects in human endometrial carcinoma cells. J Clin Endocrinol Metab, 2011, 96(3):808-816.
13. Kisfalvi K, Eibl G, Sinnett-Smith J, et al. Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res, 2009, 69(16):6539-6545.
14. Zhang ZJ, Zheng ZJ, Kan H, et al. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes:a metaanalysis. Diabetes Care, 2011, 34(10):2323-2328.
15. Memmott RM, Mercado JR, Maier CR, et al. Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev Res (Phila), 2010, 3(9):1066-1076.
16. Jung JW, Park SB, Lee SJ, et al. Metformin represses self-renewal of the human breast carcinoma stem cells via inhibition of estrogen receptor-mediated OCT4 expression. PLoS One, 2011, 6(11):e28068.
17. Zhang H, Gao C, Fang L, et al. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients:a meta-analysis. Scand J Gastroenterol, 2013, 48(1):78-87.
18. Currie CJ, Poole CD, Jenkins-Jones S, et al. Mortality after incident cancer in people with and without type 2 diabetes:impact of metformin on survival. Diabetes Care, 2012, 35(2):299-304.
19. Wang P, Kang D, Cao W, et al. Diabetes mellitus and risk of hepatocellular carcinoma:a systematic review and meta-analysis. Diabetes Metab Res Rev, 2012, 28(2):109-122.
20. Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, et al. Metformin activates an ataxia telangiectasia mutated (ATM)/Chk2-regulated DNA damage-like response. Cell Cycle, 2011, 10(9):1499-1501.
21. Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem, 2008, 114(1):63-70.
22. Zhou Q, Lui VW, Yeo W. Targeting the PI3K/Akt/mTOR pathway in hepatocellular carcinoma. Future Oncol, 2011, 7(10):1149-1167.
23. Bhalla K, Hwang BJ, Dewi RE, et al. Metformin prevents liver tumorigenesis by inhibiting pathways driving hepatic lipogenesis. Cancer Prev Res (Phila), 2012, 5(4):544-552.
24. Dowling RJ, Zakikhani M, Fantus IG, et al. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res, 2007, 67(22):10804-10812.
25. Lee CH, Subramanian S, Beck AH, et al. MicroRNA profiling of BRCA1/2 mutation-carrying and non-mutation-carrying highgrade serous carcinomas of ovary. PLoS One, 2009, 4(10):e7314.
26. Loubière C, Dirat B, Tanti JF, et al. New perspectives for metformin in cancer therapy. Ann Endocrinol (Paris), 2013, 74(2):130-136.
27. Landman GW, Kleefstra N, Van Hateren KJ, et al. Metformin associated with lower cancer mortality in type 2 diabetes:ZODIAC-16. Diabetes Care, 2010, 33(2):322-326.
28. Peter ME. Let-7 and miR-200 microRNAs:guardians against pluripotency and cancer progression. Cell Cycle, 2009, 8(6):843-852.
29. Rattan R, Graham RP, Maguire JL, et al. Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia, 2011, 13(5):483-491.
30. Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer:a consensus report. Diabetes Care, 2010, 33(7):1674-1685.

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