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Metformine et aspirine : de « nouveaux » traitements du cancer ?

Prévention et activité antitumorale

Metformin and aspirin: some “new” cancer treatments?

Prevention and anti-tumoral activity

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Oncologie

Abstract

Recently, old drugs such as the anti-diabetic agent metformin and aspirin have been found to display anti-tumoral properties. Indeed, there are more and more evidence showing that these drugs affect cancer cell proliferation and decrease tumor growth in various animal models. In this review, we summarize fundamental, pre-clinical, and clinical studies which describe metformin and aspirin action in cancer.

Résumé

La biologie de la cellule cancéreuse étant de mieux en mieux comprise, d’anciensmédicaments tels que la metformine ou l’aspirine pourraient trouver une place dans la prise en charge des maladies néoplasiques. De la recherche fondamentale à la recherche clinique, ces deux médicaments, pionniers dans leurs indications respectives, pourraient avoir une activité antitumorale. Cette revue non exhaustive résume plusieurs résultats et modes d’action de ces médicaments dans les tumeurs.

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Références

  1. Algire C, Amrein L, Bazile M, et al. (2011) Diet and tumor LKB1 expression interact to determine sensitivity to antineoplastic effects of metformin in vivo. Oncogene 30: 1174–1182

    Article  PubMed  CAS  Google Scholar 

  2. Algire C, Amrein L, Zakikhani M, et al. (2010) 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 17: 351–360

    Article  PubMed  CAS  Google Scholar 

  3. Algra A, Rothwell PM. (2012) Effects of regular aspirin on long-term cancer incidence and metastasis: a systemic comparison of evidence from observational studies versus randomised trials. Lancet 13: 518–527

    Article  CAS  Google Scholar 

  4. Anisimov VN, Berstein LM, Egormin PA, et al. (2005) Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 40: 685–693

    Article  PubMed  CAS  Google Scholar 

  5. Arai M, Uchiba M, Komura H, et al. (2010) Metformin, an antidiabetic agent, suppresses the production of tumor necrosis factor and tissue factor by inhibiting early growth response factor-1 expression in human monocytes in vitro. J Pharmacol Exp Ther 334: 206–213

    Article  PubMed  CAS  Google Scholar 

  6. Asano TK, McLeod RS (2004) Nonsteroidal anti-inflammatory drugs and aspirin for the prevention of colo-rectal adenomas and cancer: a systemic review. Dis Colon Rectum 47: 665–673

    Article  PubMed  CAS  Google Scholar 

  7. Azoulay L, Dell’Aniello S, Gagnon B, et al. (2011) Metformin and the incidence of prostate cancer in patients with type 2 diabetes. Cancer Epidemiol Biomarkers Prev 20: 337–344

    Article  PubMed  CAS  Google Scholar 

  8. Baron JA, Cole BF, Sandler RS, et al. (2003) A randomised trial of aspirin to prevent colorectal adenomas. N Engl J Med 348: 891–899

    Article  PubMed  CAS  Google Scholar 

  9. Ben Sahra I, Laurent K, Giuliano S, et al. (2010) Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res 70: 2465–2475

    Article  PubMed  CAS  Google Scholar 

  10. Ben Sahra I, Laurent K, Loubat A, et al. (2008) The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 27: 3576–3586

    Article  PubMed  CAS  Google Scholar 

  11. Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, et al. (2010) Metformin in cancer therapy: a new perspective for an old antidiabetic drug? Mol Cancer Ther 9: 1092–1099

    Article  PubMed  CAS  Google Scholar 

  12. Ben Sahra I, Regazzetti C, Robert G, et al. (2011) Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res 71: 4366–4372

    Article  PubMed  CAS  Google Scholar 

  13. Bosetti C, Gallus S, La Vecchia C (2006) Aspirin and cancer risk: an update quantitative review to 2005. Cancer Causes Control 17: 871–888

    Article  PubMed  Google Scholar 

  14. Burn J, Bishop DT, Mecklin JP, et al. (2008) Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med 359: 2567–2578

    Article  PubMed  CAS  Google Scholar 

  15. Buzzai M, Jones RG, Amaravadi RK, et al. (2007) Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 67: 6745–6752

    Article  PubMed  CAS  Google Scholar 

  16. Chan AT, Giovannucci EL, Meyerhardt JA, et al. (2005) Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 294: 914–923

    Article  PubMed  CAS  Google Scholar 

  17. Chan AT, Ogino S, Fuchs C (2007) Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356: 2131–2142

    Article  PubMed  CAS  Google Scholar 

  18. Charames GC, Bapat B (2003) Genomic instability and cancer. Curr Mol Med 3: 589–596

    Article  PubMed  CAS  Google Scholar 

  19. Cook NR, Lee JM, Gaziano JM, et al. (2005) Low-dose of aspirin in the primary prevention of cancer: the Women’s Health Study: a randomised controlled trail. JAMA 294: 47–55

    Article  PubMed  CAS  Google Scholar 

  20. Cuzick J, Otto F, Baron J, et al. (2009) Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet 10: 501–507

    Article  CAS  Google Scholar 

  21. Derry S, Loke YK (2000) Risk of gastrointestinal haemorrhage with long-term use of aspirin: meta-analysis. BMJ 321: 1183–1187

    Article  PubMed  CAS  Google Scholar 

  22. Din FV, Dunlop MG, Stark LA, et al. (2004) Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B signalling and apoptosis. Br J Cancer 91: 381–388

    PubMed  CAS  Google Scholar 

  23. Din FV, Theodoratou E, Farrington S, et al. (2010) Effect of aspirin and NSAIDs on risk and survival from colorectal cancer. Gut 59: 1670–1679

    Article  PubMed  CAS  Google Scholar 

  24. Din FV, Valanciute A, Houde VP, et al. (2012) Aspirin inhibits mTOR signaling, activates AMP-Activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 142: 1504–1515

    Article  PubMed  CAS  Google Scholar 

  25. Dowling RJ, Zakikhani M, Fantus IG, et al. (2007) Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67: 10804–10812

    Article  PubMed  CAS  Google Scholar 

  26. Egan DF, Shackelford DB, Mihaylova MM, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331: 456–461

  27. Evans JM, Donnelly LA, Emslie-Smith AM, et al. (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330: 1304–1305

    Article  PubMed  Google Scholar 

  28. Farrell B, Godwin J, Richards S, et al. (1991) The United Kingdom transient ischaemic attack (UK-TIA) aspirin trail: final results. J Neurol Neurosurg Psychiatry 54: 1044–1054

    Article  PubMed  CAS  Google Scholar 

  29. Flossmann E, Rothwell PM, on behalf of the British Doctors Aspirin Trial and the UK-TIA Aspirin Trial (2007) Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 369: 1603–1613

    Article  PubMed  CAS  Google Scholar 

  30. Foretz M, Hebrard S, Leclerc J, et al. (2010) Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 120: 2355–2369

    Article  PubMed  CAS  Google Scholar 

  31. Gallagher EJ, Leroith D (2011) Minireview: IGF, insulin, and cancer. Endocrinology 152: 2546–2551

    Article  PubMed  CAS  Google Scholar 

  32. Gann PH, Manson JE, Glyn RJ, et al. (1993) Low-dose aspirin and incidence of colorectal tumors in a randomised trial. J Natl Cancer Inst 85: 1220–1224

    Article  PubMed  CAS  Google Scholar 

  33. Giovannucci E, Harlan DM, Archer MC, et al. (2010) Diabetes and cancer: a consensus report. CA Cancer J Clin 60: 207–221

    Article  PubMed  Google Scholar 

  34. Gonzàles-Pérez A, Garcia Rodrigues LA, Lopez-Ridaura R (2003) Effects of nonsteroidal anti inflammatory drugs on cancers sites other than the colon and rectum: a meta-analysis. BMC Cancer 3: 28

    Article  Google Scholar 

  35. Goodwin PJ, Stambolic V, Lemieux J, et al. (2011) Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anticancer agents. Breast Cancer Res Treat 126: 215–220

    Article  PubMed  CAS  Google Scholar 

  36. Hadad S, Iwamoto T, Jordan L, et al. (2011) Evidence for biological effects of metformin in operable breast cancer: a preoperative, window-of-opportunity, randomised trial. Breast Cancer Res Treat 128: 783–794

    Article  PubMed  CAS  Google Scholar 

  37. Hanhan D, Weinberg RA (2001) Hallmarks of cancer: the next generation. Cell 144: 646–674

    Article  Google Scholar 

  38. Hattori Y, Suzuki K, Hattori S, et al. (2006) Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMPactivated protein kinase activation in vascular endothelial cells. Hypertension 47: 1183–1188

    Article  PubMed  CAS  Google Scholar 

  39. He XX, Tu SM, Lee MH, et al. (2011) Thiazolidinediones and metformin associated with improved survival of diabetic prostate cancer patients. Ann Oncol [Epub ahead of print]

    Google Scholar 

  40. Hirsch HA, Iliopoulos D, Tsichlis PN, et al. (2009) Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 69: 7507–7511

    Article  PubMed  CAS  Google Scholar 

  41. Hosono K, Endo H, Takahashi H, et al. (2010) Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila Pa) 3: 1077–1083

    Article  CAS  Google Scholar 

  42. Hwang YP, Jeong HG (2010) Metformin blocks migration and invasion of tumour cells by inhibition of matrix metalloproteinase-9 activation through a calcium and protein kinase C alpha-dependent pathway: phorbol-12-myristate-13-acetateinduced/extracellular signal-regulated kinase/ activator protein-1. Br J Pharmacol 160: 1195–1211

    Article  PubMed  CAS  Google Scholar 

  43. IARC Handbooks of cancer prevention (1997) Non-steroidal anti-inflammatory dugs, vol1. International Agency for Research on Cancer, Lyon

    Google Scholar 

  44. Jacobs EJ, Thun MJ, Bain EB, et al. (2007) A large cohorts study of longterm daily use of adult-strength aspirin and cancer incidence. J Natl Cancer Inst 99: 608–615

    Article  PubMed  CAS  Google Scholar 

  45. Janjetovic K, Vucicevic L, Misirkic M, et al. (2011) Metformin reduces cisplatin mediated apoptotic death of cancer cells through AMPK-independent activation of AKT. Eur J Pharmacol 651: 41–50

    Article  PubMed  CAS  Google Scholar 

  46. Jiralerspong S, Palla SL, Giordano SH, et al. (2009) Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27: 3297–3302

    Article  PubMed  CAS  Google Scholar 

  47. Jones RG, Plas DR, Kubek S, et al. (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18: 283–293

    Article  PubMed  CAS  Google Scholar 

  48. Kalender A, Selvaraj A, Kim SY, et al. (2010) Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPasedependent manner. Cell Metab 11: 390–401

    Article  PubMed  CAS  Google Scholar 

  49. Kim HG, Hien TT, Han EH, et al. (2011) Metformin inhibits P-glycoprotein expression via the NF-kappaB pathway and CRE transcriptional activity through AMPK activation. Br J Pharmacol 162: 1096–1108

    Article  PubMed  CAS  Google Scholar 

  50. Lee MS, Hsu CC, Wahlqvist ML, et al. (2011) 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 11: 20

    Article  PubMed  CAS  Google Scholar 

  51. Liao X, Lockheed P, Nishihara R, et al. (2012) Aspirin use, tumour PI3KCA mutation and colorectal-cancer survival. N Engle J Med 367: 1596–1606

    Article  CAS  Google Scholar 

  52. Libby G, Donnelly LA, Donnan PT, et al. (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32: 1620–1625

    Article  PubMed  CAS  Google Scholar 

  53. Medical Research Council’s General Practice Research Framework (1998) Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarine and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 351: 233–241

    Article  Google Scholar 

  54. Memmott RM, Mercado JR, Maier CR, et al. (2010) Metformin prevents tobacco carcinogen: induced lung tumorigenesis. Cancer Prev Res (Phila) 3: 1066–1076

    Article  CAS  Google Scholar 

  55. Miliaras S, Miliaras D, Vrettou E, et al. (2004) The effect of aspirin and high fibre diet on colorectal carcinoma: a comparative experimental study. Tech Coloproctol 8(suppl 1): S59–S61

    Article  PubMed  Google Scholar 

  56. Moreno-Navarrete JM, Ortega FJ, Rodriguez-Hermosa JI, et al. (2011) OCT1 Expression in adipocytes could contribute to increased metformin action in obese subjects. Diabetes 60: 168–176

    Article  PubMed  CAS  Google Scholar 

  57. Oshima M, Dinchuk JE, Kargman SL, et al. (1996) Suppression of intestinal polyposis in Apc delta 716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87: 803–809

    Article  PubMed  CAS  Google Scholar 

  58. Pearce EL, Walsh MC, Cejas PJ, et al. (2009) Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460: 103–107

    Article  PubMed  CAS  Google Scholar 

  59. Peto R, Gray R, Collin R, et al. (1988) Lowdose aspirin in British male doctors. BMJ 296: 313–316

    Article  PubMed  CAS  Google Scholar 

  60. Rao CV, Rivenson A, Simi B, et al. (1995) Chemoprevention of colon carcinogenesis by sulindac, a non-steroidal antiinflammatory agent. Cancer Res 55: 1462–1472

    Google Scholar 

  61. Rattan R, Graham RP, Maguire JL, et al. (2010) Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia 13: 483–491

    Google Scholar 

  62. Rothwell P, Fowkes FG, Belch JF, et al. (2011) Effects of daily aspirin on longterm risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377: 31–41

    Article  PubMed  CAS  Google Scholar 

  63. Rothwell PM, Price JF, Fowkes FG, et al. (2012) Short-term effects of daily aspirin on cancer incidence, mortality, and nonvascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 379: 1602–1612

    Article  PubMed  CAS  Google Scholar 

  64. Rothwell PM, Wilson M, Elwin CE, et al. (2010) Long-term effect of aspirin on colorectal cancer incidence and mortality: 20 year follow-up of five randomised trials. Lancet 376: 1741–1750

    Article  PubMed  CAS  Google Scholar 

  65. Sandler RS, Halabi S, Baron JA, et al. (2003) A randomised trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 348: 883–890

    Article  PubMed  CAS  Google Scholar 

  66. Schneider MB, Matsuzaki H, Haorah J, et al. (2001) Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology 120: 1263–1270

    Article  PubMed  CAS  Google Scholar 

  67. Schott S, Bierhaus A, Schuetz F, et al. (2011) Therapeutic effects of metformin in breast cancer: involvement of the immune system? Cancer Immunol Immunother 60: 1221–1225

    Article  PubMed  CAS  Google Scholar 

  68. Serebruany VL, Steinhul SR, Berger PB, et al. (2005) Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients in 31 randomised controlled trials. Am J Cardiol 95: 1218–1222

    Article  PubMed  CAS  Google Scholar 

  69. Taketo MM (1998) Cyclooxygenase-2 inhibitors in tumorigenesis (Part II). J Natl Cancer Inst 90: 1609–1620

    Article  PubMed  CAS  Google Scholar 

  70. Tan BK, Adya R, Chen J, et al. (2011) Metformin treatment exerts antiinvasive and antimetastatic effects in human endometrial carcinoma cells. J Clin Endocrinol Metab 96: 808–816

    Article  PubMed  CAS  Google Scholar 

  71. Thun MJ, Henley SJ, Patrona C (2002) Nonsteroidal anti-inflammatory drugs as cancer agents: mechanistic, pharmacologic and clinical issues. J Natl Cancer Inst 94: 252–266

    Article  PubMed  CAS  Google Scholar 

  72. Yao M, Zhou W, Sangha S, et al. (2011) Effects of nonselective cyclooxygenase inhibition with low dose ibuprofen on tumor growth, angiogenesis, metastasis, and survival in a mouse model of colorectal cancer. Clin Cancer Res 11: 1618–1628

    Article  Google Scholar 

  73. Yasmeen A, Beauchamp MC, Piura E, et al. (2011) Induction of apoptosis by metformin in epithelial ovarian cancer: involvement of the Bcl-2 family proteins. Gynecol Oncol 121: 492–498

    Article  PubMed  CAS  Google Scholar 

  74. Zakikhani M, Dowling R, Fantus IG, et al. (2006) Metformin is an AMP kinasedependent growth inhibitor for breast cancer cells. Cancer Res 66: 10269–10273

    Article  PubMed  CAS  Google Scholar 

  75. Zhang L, Yu J, Park BH, et al. (2000) Role of BAX in the apoptotic response to anticancer agents. Science 290: 989–992

    Article  PubMed  CAS  Google Scholar 

  76. Zhang Z, DuBois RN (2000) PAR4, a proapoptotic gene, is regulated by NSAID in human colon carcinoma cells. Gastroenterology 118: 1012–1017

    Article  PubMed  CAS  Google Scholar 

  77. Zhou G, Myers R, Li Y, et al. (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108: 1167–1174

    PubMed  CAS  Google Scholar 

  78. Zhou K, Bellenguez C, Spencer CC, et al. (2011) Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet 43: 117–120

    Article  PubMed  CAS  Google Scholar 

  79. Zhuang Y, Miskimins WK (2010) Metformin induces both caspase-dependent and poly(ADP-ribose) polymerase-dependent cell death in breast cancer cells. Mol Cancer Res 9: 603–615

    Article  Google Scholar 

  80. Zimmermann KC, Waterhouse NJ, Goldstein JC, et al. (2000) Aspirin induces apoptosis through release of cytochrome c from mitochondria. Neoplasia 2: 505–513

    Article  PubMed  CAS  Google Scholar 

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  1. Service d’oncologie médicale, hôpital Cochin, 27, rue du Faubourg-Saint-Jacques, F-75005, Paris, France

    J. Arrondeau

  2. équipe 7 bâtiment Archimed, Université de Nice-Sophia-Antipolis, Inserm U1065, 151, route de Saint-Antoine-de-Ginestière, BP 23194, F-06204, Nice cedex 03, France

    F. Bost

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Arrondeau, J., Bost, F. Metformine et aspirine : de « nouveaux » traitements du cancer ?. Oncologie 15, 480–489 (2013). https://doi.org/10.1007/s10269-013-2319-1

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