The Drug Virtually Everyone Should Ask their Doctor AboutNovember 2010
By Julius Goepp, MD
More men and women die from lung cancer than from any other malignancy. In 2006, lung cancer caused more deaths than breast cancer, colon cancer, and prostate cancer combined.51 Clearly, new solutions to fighting lung cancer are greatly needed. Emerging research suggests that metformin may offer hope in combating this deadly disease.
In a recent study, scientists examined the effects of metformin on an experimental form of lung cancer that is especially aggressive in obese subjects with high blood sugar. Animal subjects received either a control diet or a high-energy diet that typically leads to weight gain and insulin resistance, and selected subjects received metformin in their drinking water. After three weeks, the subjects were injected with lung cancer cells. Seventeen days later, animals on the high-energy diet had tumors that were twice the volume of animals on the control diet. Metformin significantly attenuated tumor growth in subjects consuming a high-energy diet. Metformin led to increased phosphorylation of AMPK and attenuated the increased insulin receptor activation association with a high-energy diet—both of which would be expected to decrease cancer proliferation.3
Additional research suggests that metformin may enhance the effects of radiation therapy in eradicating lung and other cancers.52
While further studies are needed, these findings suggest that metformin may offer promise in the fight against lung cancer.
The list of cancers against which metformin is protective is growing rapidly, now including cancers of the prostate, pancreas, liver, lung, and other tissues.3,16,95,96 Since metformin acts by multiple pathways, most of which are fundamental to every kind of cancer, there’s no reason to think that these results won’t in fact be generalizable to every human malignancy.
The key fact about metformin is its ability, shared with other nutraceuticals but rare among other prescription drugs, to potently mimic the effects of calorie restriction. Metformin’s calorie restriction-like effects trigger profound cellular changes in every mammalian tissue, activating tumor suppressing mechanisms while suppressing tumor activating mechanisms. By lowering chronic blood sugar levels and limiting lifetime exposure to insulin and insulin-like growth factors, metformin can directly reduce cancer risks related to these factors.
The wealth of evidence of metformin’s anti-cancer activity is now expanding to include not only those with diabetes or pre-diabetic conditions, but also people who are apparently otherwise healthy. This means that anyone who is serious about a comprehensive approach to cancer prevention should give serious consideration to using metformin just as faithfully as they use other calorie restriction-mimetic supplements.
Those seeking to gain the longevity benefits associated with reduced glucose and insulin levels can benefit tremendously from metformin.
As you read in last month’s issue, optimal fasting glucose should be around 80 mg/dL. Metformin can help aging humans achieve these lower and healthier glucose levels. Typical doses are 250 mg to 850 mg taken before two or three meals each day. Refer to the box on the following page for information about who should not take metformin.
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
1. Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR. Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care. 2010 Jun;33(6):1304-8.
2. Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009 Aug;137(2):482-8.
3. Algire C, Zakikhani M, Blouin MJ, Shuai JH, Pollak M. Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth. Endocr Relat Cancer. 2008 Sep;15(3):833-9.
4. Witters LA. The blooming of the French lilac. J Clin Invest. 2001 Oct;108(8):1105-7.
5. Vuksan V, Sievenpiper JL. Herbal remedies in the management of diabetes: lessons learned from the study of ginseng. Nutr Metab Cardiovasc Dis. 2005 Jun;15(3):149-60.
6. Hundal RS, Inzucchi SE. Metformin: new understandings, new uses. Drugs. 2003;63(18):1879-94.
7. Johnson JA, Majumdar SR, Simpson SH, Toth EL. Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care. 2002 Dec;25(12):2244-8.
8. Gosmanova EO, Canada RB, Mangold TA, Rawls WN, Wall BM. Effect of metformin-containing antidiabetic regimens on all-cause mortality in veterans with type 2 diabetes mellitus. Am J Med Sci. 2008 Sep;336(3):241-7.
9. Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care. 2005 Oct;28(10):2345-51.
10. Evans JM, Ogston SA, Emslie-Smith A, Morris AD. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia. 2006 May;49(5):930-6.
11. Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 2006 Feb;29(2):254-8.
12. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009 Sep;52(9):1766-77.
13. Duncan BB, Schmidt MI. Metformin, cancer, alphabet soup, and the role of epidemiology in etiologic research. Diabetes Care. 2009 Sep;32(9):1748-50.
14. Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care. 2010 Feb;33(2):322-6.
15. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005 Jun 4;330(7503):1304-5.
16. Czyzyk A, Szczepanik Z. Diabetes mellitus and cancer. Eur J Intern Med. 2000 Oct;11(5):245-52.
17. Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer. Endocr Relat Cancer. 2009 Dec;16(4):1103-23.
18. 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 Mar 21;9(6).
19. Anisimov VN, Egormin PA, Piskunova TS, et al. Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo. Cell Cycle. 2010 Jan 1;9(1):188-97.
20. Phoenix KN, Vumbaca F, Fox MM, Evans R, Claffey KP. Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy. Breast Cancer Res Treat. 2009 Nov 22.
21. Brown KA, Hunger NI, Docanto M, Simpson ER. Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase. Breast Cancer Res Treat. 2010 Mar 19.
22. Yurekli BS, Karaca B, Cetinkalp S, Uslu R. Is it the time for metformin to take place in adjuvant treatment of Her-2 positive breast cancer? Teaching new tricks to old dogs. Med Hypotheses. 2009 Oct;73(4):606-7.
23. Gonzalez-Angulo AM, Meric-Bernstam F. Metformin: a therapeutic opportunity in breast cancer. Clin Cancer Res. 2010 Mar 15;16(6):1695-700.
24. Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. Cell Cycle. 2009 Jan 1;8(1):88-96.
25. Olayioye MA. Update on HER-2 as a target for cancer therapy: intracellular signaling pathways of ErbB2/HER-2 and family members. Breast Cancer Res. 2001;3(6):385-9.
26. Zhuang Y, Miskimins WK. Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1. J Mol Signal. 2008;3:18.
27. Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009 Oct 1;69(19):7507-11.
28. Alimova IN, Liu B, Fan Z, et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle. 2009 Mar 15;8(6):909-15.
29. Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009 Jul 10;27(20):3297-302.
30. Liu B, Fan Z, Edgerton SM, et al. Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle. 2009 Jul 1;8(13):2031-40.
31. Martin-Castillo B, Dorca J, Vazquez-Martin A, et al. Incorporating the antidiabetic drug metformin in HER2-positive breast cancer treated with neo-adjuvant chemotherapy and trastuzumab: an ongoing clinical-translational research experience at the Catalan Institute of Oncology. Ann Oncol. 2010 Jan;21(1):187-9.
32. Garcia A, Tisman G. Metformin, B(12), and enhanced breast cancer response to chemotherapy. J Clin Oncol. 2010 Jan 10;28(2):e19; author reply e20.
33. Kacalska O, Krzyczkowska-Sendrakowska M, Milewicz T, et al. Molecular action of insulin-sensitizing agents. Endokrynol Pol. 2005 May-Jun;56(3):308-13.
34. Session DR, Kalli KR, Tummon IS, Damario MA, Dumesic DA. Treatment of atypical endometrial hyperplasia with an insulin-sensitizing agent. Gynecol Endocrinol. 2003 Oct;17(5):405-7.
35. Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, Bae-Jump VL. Metformin is a potent inhibitor of endometrial cancer cell proliferation--implications for a novel treatment strategy. Gynecol Oncol. 2010 Jan;116(1):92-8.
36. Stanosz S. An attempt at conservative treatment in selected cases of type I endometrial carcinoma (stage I a/G1) in young women. Eur J Gynaecol Oncol. 2009;30(4):365-9.
37. Guastamacchia E, Resta F, Triggiani V, et al. Evidence for a putative relationship between type 2 diabetes and neoplasia with particular reference to breast cancer: role of hormones, growth factors and specific receptors. Curr Drug Targets Immune Endocr Metabol Disord. 2004 Mar;4(1):59-66.
38. Zakikhani M, Dowling RJ, Sonenberg N, Pollak MN. The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res (Phila Pa). 2008 Oct;1(5):369-75.
39. Ben Sahra I, 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 Jun 5;27(25):3576-86.
40. Raina K, Blouin MJ, Singh RP, et al. Dietary feeding of silibinin inhibits prostate tumor growth and progression in transgenic adenocarcinoma of the mouse prostate model. Cancer Res. 2007 Nov 15;67(22):11083-91.
41. Khan NA, Nishimura K, Aires V, et al. Docosahexaenoic acid inhibits cancer cell growth via p27Kip1, CDK2, ERK1/ERK2, and retinoblastoma phosphorylation. J Lipid Res. 2006 Oct;47(10):2306-13.
42. Johnson CS, Muindi JR, Hershberger PA, Trump DL. The antitumor efficacy of calcitriol: preclinical studies. Anticancer Res. 2006 Jul-Aug;26(4A):2543-9.
43. Ben Sahra I, Laurent K, Giuliano S, et al. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res. 2010 Mar 15;70(6):2465-75.
44. Wright JL, Stanford JL. Metformin use and prostate cancer in Caucasian men: results from a population-based case-control study. Cancer Causes Control. 2009 Nov;20(9):1617-22.
45. Rozengurt E, Sinnett-Smith J, Kisfalvi K. Crosstalk between insulin/insulin-like growth factor-1 receptors and G protein-coupled receptor signaling systems: a novel target for the antidiabetic drug metformin in pancreatic cancer. Clin Cancer Res. 2010 Apr 13.
46. Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E. Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res. 2009 Aug 15;69(16):6539-45.
47. Wang LW, Li ZS, Zou DW, Jin ZD, Gao J, Xu GM. Metformin induces apoptosis of pancreatic cancer cells. World J Gastroenterol. 2008 Dec 21;14(47):7192-8.
48. Yamagishi S, Nakamura K, Inoue H, Kikuchi S, Takeuchi M. Possible participation of advanced glycation end products in the pathogenesis of colorectal cancer in diabetic patients. Med Hypotheses. 2005;64(6):1208-10.
49. Mountjoy KG, Finlay GJ, Holdaway IM. Effects of metformin and glibenclamide on insulin receptors in fibroblasts and tumor cells in vitro. J Endocrinol Invest. 1987 Dec;10(6):553-7.
50. Algire C, Amrein L, Zakikhani M, Panasci L, Pollak M. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer. 2010 Jun;17(2):351-60.
51. Available at: http://www.cdc.gov/cancer/lung/statistics/. Accessed August 3, 2010.
52. Sanli T, Rashid A, Liu C,et al. Ionizing radiation activates AMP-activated kinase (AMPK): a target for radiosensitization of human cancer cells. Int J Radiat Oncol Biol Phys. 2010 Jul 7.
53. Mehnert H. Metformin, the rebirth of a biguanide: mechanism of action and place in the prevention and treatment of insulin resistance. Exp Clin Endocrinol Diabetes. 2001;109 Suppl 2:S259-64.
54. Desilets AR, Dhakal-Karki S, Dunican KC. Role of metformin for weight management in patients without type 2 diabetes. Ann Pharmacother. 2008 Jun;42(6):817-26.
55. Golay A. Metformin and body weight. Int J Obes (Lond). 2008 Jan;32(1):61-72.
56. Brame L, Verma S, Anderson T, Lteif A, Mather K. Insulin resistance as a therapeutic target for improved endothelial function: metformin. Curr Drug Targets Cardiovasc Haematol Disord. 2004 Mar;4(1):53-63.
57. Tan BK, Heutling D, Chen J, et al. Metformin decreases the adipokine vaspin in overweight women with polycystic ovary syndrome concomitant with improvement in insulin sensitivity and a decrease in insulin resistance. Diabetes. 2008 Jun;57(6):1501-7.
58. Ehret M, Goethe J, Lanosa M, Coleman CI. The effect of metformin on anthropometrics and insulin resistance in patients receiving atypical antipsychotic agents: a meta-analysis. J Clin Psychiatry. 2010 Apr 6.
59. Ellinger LK, Ipema HJ, Stachnik JM. Efficacy of metformin and topiramate in prevention and treatment of second-generation antipsychotic-induced weight gain. Ann Pharmacother. 2010 Apr;44(4):668-79.
60. Aghahosseini M, Aleyaseen A, Safdarian L, Moddaress-Hashemi S, Mofid B, Kashani L. Metformin 2,500 mg/day in the treatment of obese women with polycystic ovary syndrome and its effect on weight, hormones, and lipid profile. Arch Gynecol Obstet. 2010 Jul 2.
61. Wysocki PJ, Wierusz-Wysocka B. Obesity, hyperinsulinemia and breast cancer: novel targets and a novel role for metformin. Expert Rev Mol Diagn. 2010 May;10(4):509-19.
62. Anisimov VN, Berstein LM, Egormin PA, et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol. 2005 Aug-Sep;40(8-9):685-93.
63. Wilson DM, Abrams SH, Aye T, et al. Metformin extended release treatment of adolescent obesity: A 48-week randomized, double-blind, placebo-controlled trial with 48-week follow-up. Arch Pediatr Adolesc Med. 2010 Feb;164(2):116-23.
64. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008 Dec;8(12):915-28.
65. Sanz P. AMP-activated protein kinase: structure and regulation. Curr Protein Pept Sci. 2008 Oct;9(5):478-92.
66. Jiralerspong S, Gonzalez-Angulo AM, Hung MC. Expanding the arsenal: metformin for the treatment of triple-negative breast cancer? Cell Cycle. 2009 Sep 1;8(17):2681.
67. Luo Z, Zang M, Guo W. AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncol. 2010 Mar;6(3):457-70.
68. 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 Sep;32(9):1620-5.
69. Wang W, Guan KL. AMP-activated protein kinase and cancer. Acta Physiol (Oxf). 2009 May;196(1):55-63.
70. Vazquez-Martin A, Oliveras-Ferraros C, Lopez-Bonet E, Menendez JA. AMPK: Evidence for an energy-sensing cytokinetic tumor suppressor. Cell Cycle. 2009 Nov 15;8(22):3679-83.
71. Oliveras-Ferraros C, Vazquez-Martin A, Menendez JA. Genome-wide inhibitory impact of the AMPK activator metformin on [kinesins, tubulins, histones, auroras and polo-like kinases] M-phase cell cycle genes in human breast cancer cells. Cell Cycle. 2009 May 15;8(10):1633-6.
72. Rattan R, Giri S, Hartmann L, Shridhar V. Metformin attenuates ovarian cancer cell growth in an AMP- kinase dispensable manner. J Cell Mol Med. 2009 Oct 29.
73. Kim DH, Sarbassov DD, Ali SM, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002 Jul 26;110(2):163-75.
74. Tokunaga C, Yoshino K, Yonezawa K. mTOR integrates amino acid- and energy-sensing pathways. Biochem Biophys Res Commun. 2004 Jan 9;313(2):443-6.
75. Choo AY, Kim SG, Vander Heiden MG, et al. Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. Mol Cell. 2010 May 28;38(4):487-99.
76. Kalender A, Selvaraj A, Kim SY, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010 May 5;11(5):390-401.
77. Sakuma K, Yamaguchi A. Molecular mechanisms in aging and current strategies to counteract sarcopenia. Curr Aging Sci. 2010 Jul 1;3(2):90-101.
78. Sudarsanam S, Johnson DE. Functional consequences of mTOR inhibition. Curr Opin Drug Discov Devel. 2010 Jan;13(1):31-40.
79. Blagosklonny MV. Calorie restriction: decelerating mTOR-driven aging from cells to organisms (including humans). Cell Cycle. 2010 Feb;9(4):683-8.
80. Ghosh HS, McBurney M, Robbins PD. SIRT1 negatively regulates the mammalian target of rapamycin. PLoS One. 2010;5(2):e9199.
81. Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol (Oxf). 2009 May;196(1):65-80.
82. Jalving M, Gietema JA, Lefrandt JD, et al. Metformin: Taking away the candy for cancer? Eur J Cancer. 2010 Jul 23.
83. Available at:http://www.sciencedaily.com/releases/2010/05/100504124344.htm#.Accessed July 28, 2010.
84. Saeedi R, Parsons HL, Wambolt RB, et al. Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms. Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2497-506.
85. Ota S, Horigome K, Ishii T, et al. Metformin suppresses glucose-6-phosphatase expression by a complex I inhibition and AMPK activation-independent mechanism. Biochem Biophys Res Commun. 2009 Oct 16;388(2):311-6.
86. Miller RA, Birnbaum MJ. An energetic tale of AMPK-independent effects of metformin. J Clin Invest. 2010 Jul 1;120(7):2267-70.
87. Foretz M, Hebrard S, Leclerc J, 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 Jul 1;120(7):2355-69.
88. Vazquez-Martin A, Oliveras-Ferraros C, del Barco S, Martin-Castillo B, Menendez JA. mTOR inhibitors and the anti-diabetic biguanide metformin: new insights into the molecular management of breast cancer resistance to the HER2 tyrosine kinase inhibitor lapatinib (Tykerb). Clin Transl Oncol. 2009 Jul;11(7):455-9.
89. Monaco AP. The role of mTOR inhibitors in the management of posttransplant malignancy. Transplantation. 2009 Jan 27;87(2):157-63.
90. Albert S, Serova M, Dreyer C, Sablin MP, Faivre S, Raymond E. New inhibitors of the mammalian target of rapamycin signaling pathway for cancer. Expert Opin Investig Drugs. 2010 Aug;19(8):919-30.
91. Zakikhani M, Blouin MJ, Piura E, Pollak MN. Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast Cancer Res Treat. 2010 Aug;123(1):271-9.
92. Available at: http://www.medicalnewstoday.com/articles/191197.php. Accessed July 29, 2010.
93. Available at: http://www.pdrhealth.com/drugs/rx/rx-mono.aspx?contentFileName=pra1968.html&contentName=PrandiMet&contentId=595. Accessed August 2, 2010.
94. Available at: http://www.rxlist.com/glucophage-drug.htm. Accessed August 3, 2010
95. Donadon V, Balbi M, Casarin P, Vario A, Alberti A. Association between hepatocellular carcinoma and type 2 diabetes mellitus in Italy: potential role of insulin. World J Gastroenterol. 2008 Oct 7;14(37):5695-700.
96. Donadon V, Balbi M, Zanette G. Hyperinsulinemia and risk for hepatocellular carcinoma in patients with chronic liver diseases and Type 2 diabetes mellitus. Expert Rev Gastroenterol Hepatol. 2009 Oct;3(5):465-7.
97. Available at: http://diabetes.emedtv.com/metformin/metformin-and-tsh-levels.html. Accessed August 31, 2010.
98. Available at: http://care.diabetesjournals.org/content/32/9/1589.full. Accessed August 31, 2010.
99. Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev Res. 2010 Sept; 3:1066.
100. Hosono K, Endo H, Takahashi H, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res. 2010 Sept; 3:1077.