Role of Metformin in Suppressing 1,2-Dimethylhydrazine-Induced Colon Cancer in Diabetic and Non-Diabetic Mice: Effect on Tumor Angiogenesis and Cell Proliferation
Several studies indicated that type 2 diabetes mellitus and insulin resistance are associated with increased colon cancer risk. Recently, studies suggest that metformin can reduce cancer risk in diabetic or non-diabetic patients with unclear mechanisms. This work aimed to determine the effect of metformin on chemically-induced colon cancer in mice. Colon cancer was induced using 1,2-dimethylhydrazine (DMH, 20 mg/kg/week, s.c.) for fifteen weeks. Experiment I: healthy mice were fed with basal diet for four weeks and then allocated into seven groups, (i) saline, (ii) DMH, (iii) oxaliplatin, (iv–v): metformin (100 or 200 mg/kg) and (vi–vii): oxaliplatin+metformin (100 or 200 mg/kg), respectively. Experiment II: type 2 diabetes mellitus was induced by injection of STZ (30 mg/kg) after four weeks of high-fat feeding and then mice were allocated into seven groups similar to those reported in experiment I. Examination of the colonic tissue at the end of the experiment highlighted an increase in angiogenic markers and cell proliferation and showed a greater immunostaining for insulin growth factor I receptors and CD34 in the colon of diabetic mice compared to non-diabetics. In general, metformin downregulated tumor angiogenesis and augmented the antitumor effect of oxaliplatin. Overall, the current results showed that metformin protected against DMH-induced colon cancer in non-diabetic and diabetic mice. This therapeutic effect was, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.
References
[1]
Jemal A, Siegel R, Ward E, Hao Y, Xu J, et al. (2008) Cancer statistics. CA Cancer J Clin 58: 71–96. doi: 10.3322/ca.2007.0010
[2]
Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ (2004) Diabetes mellitus as a predictor of cancer mortality in a large cohort of U.S. adults. Am J Epidemiol 159: 1160–1167. doi: 10.1093/aje/kwh161
[3]
El-Serag H, Hampel H, Javadi F (2006) The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 4: 369–380. doi: 10.1016/j.cgh.2005.12.007
[4]
Larsson SC, Orsini N, Wolk A (2005) Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst 97: 1679–1687. doi: 10.1093/jnci/dji375
[5]
Friberg E, Orsini N, Mantzoros CS, Wolk A (2007) Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia 50: 1365–1374. doi: 10.1007/s00125-007-0681-5
[6]
Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1: 27–31. doi: 10.1038/nm0195-27
[7]
Hanahan D (1998) A flanking attack on cancer. Nat Me 4: 13–14. doi: 10.1038/nm0198-013
[8]
Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, et al. (2004) Vascular Endothelial Growth Factor and Angiogenesis. Pharmacol Rev 56: 549–580. doi: 10.1124/pr.56.4.3
[9]
Chiarelli F, Spagnoli A, Basciani F, Tumini S, Mezzetti A, et al. (2000) Vascular endothelial growth factor (VEGF) in children, adolescents and young adults with Type 1 diabetes mellitus: relation to glycemic control and microvascular complications. Diabet Med 17: 650–656. doi: 10.1046/j.1464-5491.2000.00350.x
[10]
Ferrara N, Houck K, Jakeman L, Leung DW (1992) Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev 13: 18–32. doi: 10.1210/edrv-13-1-18
[11]
Ikemura M, Nishikawa M, Kusamori K, Fukuoka M, Yamashita F, et al. (2013) Pivotal role of oxidative stress in tumor metastasis under diabetic conditions in mice, Sakyo-ku, Kyoto. Jap J Controlled Release 170: 191–197. doi: 10.1016/j.jconrel.2013.05.028
[12]
Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8: 915–928. doi: 10.1038/nrc2536
[13]
Boyd DB (2003) Insulin and cancer. Integr Cancer Ther 2: 315–329. doi: 10.1177/1534735403259152
[14]
Haisa M (2013) The type 1 insulin-like growth factor receptor signalling system and targeted tyrosine kinase inhibition in cancer. J Int Med Res 41: 253–264. doi: 10.1177/0300060513476585
[15]
Arcaro A (2013) Targeting the insulin-like growth factor-1 receptor in human cancer. Front Pharmacol 4: 1–8. doi: 10.3389/fphar.2013.00030
[16]
Micic D, Cvijovic G, Trajkovic V, Duntas LH, Polovina S (2011) Hormones. 10: 5–15. doi: 10.14310/horm.2002.1288
[17]
Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330: 1304–1305. doi: 10.1136/bmj.38415.708634.f7
[18]
Bowker SL, Majumdar SR, Veugelers P, Johnson JA (2006) Increased cancer related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29: 254–258. doi: 10.2337/diacare.29.02.06.dc05-1558
[19]
Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, 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. doi: 10.2337/dc08-2175
[20]
Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, et al. (2009) Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27: 3297–3302. doi: 10.1200/jco.2009.19.6410
[21]
McFarland MS, Cripps R (2010) Diabetes Mellitus and Increased Risk of Cancer: Focus on Metformin and the Insulin Analogs. Pharmacotherapy: J Human Pharmacol Drug Therapy 30: 1159–1178. doi: 10.1592/phco.30.11.1159
[22]
Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P (2005) Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: A model for type 2 diabetes and pharmacological screening. Pharmacol Res 52: 313–320. doi: 10.1016/j.phrs.2005.05.004
[23]
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, et al. (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetol 28: 412–419. doi: 10.1007/bf00280883
[24]
Colussi C, Fiumicino S, Giuliani A, Rosini S, Musiani P, et al. (2001) 1,2-dimethylhydrazine-induced colon carcinoma and Lymphoma in msh2？/？ mice. JNCI 93: 1534–1540. doi: 10.1093/jnci/93.20.1534
[25]
Rattan R, Graham RP, Maguire JL, Giri S, Shridhar V (2011) Metformin Suppresses Ovarian Cancer Growth and Metastasis with Enhancement of Cisplatin Cytotoxicity In Vivo. Neoplasia 13: 483–491.
[26]
Reagan-Shaws , Nihal M, Ahmed N (2008) Translation from animal to human studies revisited. FASEB J 22: 659–661. doi: 10.1096/fj.07-9574lsf
[27]
Rattan R, Graham RP, Maguire JL, Giri S, Shridhar V (2011) Metformin Suppresses Ovarian Cancer Growth and Metastasis with Enhancement of Cisplatin Cytotoxicity In Vivo. Neoplasia 13(5): 483–491.
[28]
Liu J, Li M, Song B, Jia C, Zhang L, et al. (2013) Metformin inhibits renal cell carcinoma in vitro and in vivo xenografts. Urol Oncol: Seminars and Original Invest 31: 264–270. doi: 10.1016/j.urolonc.2011.01.003
[29]
Janjetovic K, Harhaji-Trajkovic L, Misirkic-Marjanovic M, Vucicevic L, Stevanovic D, et al. (2011) In vitro and in vivo anti-melanoma action of metformin. Eur J Pharmacol 668: 373–382. doi: 10.1016/j.ejphar.2011.07.004
[30]
Rothenberg ML (2000) Efficacy of oxaliplatin in treatment of colorectal cancer, Oncology. 14(11): 9–14.
[31]
Banchroft JD, Stevens A, Turner DR (1996). Theory and Practice of Histological Techniques. 4th Ed. Churchil Livingstone, New York, London, San Francisco, Tokyo.
[32]
Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Relat Cancer 16: 1103–1123. doi: 10.1677/erc-09-0087
[33]
Inoue M, Iwasaki M, Otani T, Sasazuki S, Noda M, et al. (2006) Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan, Arch. Intern Med 166: 1871–1877. doi: 10.1001/archinte.166.17.1871
[34]
Barone BB, Yeh HC, Snyder CF, Peairs KS, Stein KB, et al. (2008) Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. J Am Med Assoc 300: 2754–2764. doi: 10.1001/jama.2008.824
[35]
Michels KB, Solomon CG, Hu FB, Rosner BA, Hankinson SE, et al. (2003) Type 2 diabetes and subsequent incidence of breast cancer in the Nurses' Health Study. Diabetes Care 26: 1752–1758. doi: 10.2337/diacare.26.6.1752
[36]
Will JC, Galuska DA, Vinicor F, Calle EE (1998) Colorectal cancer: another complication of diabetes mellitus? Am J Epidemiol 147: 816–825. doi: 10.1093/oxfordjournals.aje.a009534
[37]
Everhart J, Wright D (1995) Diabetes mellitus as risk factor for pancreatic cancer: a meta-analysis. JAMA 273: 1605–1609. doi: 10.1001/jama.273.20.1605
[38]
Awata K, Inoue K, Kurihara S, Ohkubo T, Watanabe M, et al. (2002) A Common Polymorphism in the 5′-Untranslated Region of the VEGF Gene Is Associated With Diabetic Retinopathy in Type 2 Diabetes. Diabetes 51: 1635–1639. doi: 10.2337/diabetes.51.5.1635
[39]
Renehan AG, Zwahlen M, Minder C, O'Dwyer ST, Shalet SM, Egger M (2004) Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363: 1346–1353. doi: 10.1016/s0140-6736(04)16044-3
[40]
Gerstein HC (2010) Does insulin therapy promote, reduce, or have a neutral effect on cancers? JAMA 303: 446–447. doi: 10.1001/jama.2010.60
[41]
Hvid H, Blouin MJ, Birman E, Damgaard J, Poulsen F, et al. (2013) Treatment with insulin analog X10 and IGF-1 increases growth of colon cancer allografts. PLoS ONE 8: e79710. doi: 10.1371/journal.pone.0079710
[42]
Kisfalvi K, Eibl G, Sinnet-Smith J, Rozengurt E (2009) Metformin disrupts crosstalk between G protein coupled-receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res 69: 2539–2545. doi: 10.1158/0008-5472.can-09-0418
[43]
Oh JS, Kucab JE, Bushel PR, Martin K, Bennett L, et al. (2002) Insulin-like growth factor-I inscribes a gene expression profile for angiogenic factors and cancer progression in breast epithelial cells. Neoplasia 4: 204–217. doi: 10.1038/sj.neo.7900229
[44]
Castleden , Shilkin Br (1979) Diet, liver function and dimethylhydrazine-induced gastrointestinal tumours in Wistar rats. J Cancer 39: 731–739.
[45]
Lewis JG, James A (1982) Effect of 1,2-Dimethylhydrazine and diethyl nitrosamine on Cell Replication and Unscheduled DMA Synthesis in Target and Non target Cell Populations in Rat Liver Following Chronic Administration. Cancer Res 42: 89–92.
[46]
Ying TS, Sarma DS, Farber E (1979) Induction of presumptive preneoplastic lesions in rat liver by a single dose of 1,2-dimethylhydrazine. Chem. Biol. Interact 28: 363–366. doi: 10.1016/0009-2797(79)90176-5
[47]
Hayes MA, Rushmore TH, Goldberg MI (1987) inhibition of hepatocarcinogenic response to 1,2dimethylhydrazine by diallyl sulfide, a component of garlic oil. Carcinogenesis 8: 1155–1157. doi: 10.1093/carcin/8.8.1155
[48]
Yilmaz A, Davis ME, Simmen RCM (1999) Reproductive performance of bulls divergently selected on the basis of blood serum insulin-like growth factor I concentration. J Anim Sci 77: 835–839. doi: 10.1016/j.theriogenology.2005.06.018
[49]
Jackson PE, Cooper DP, O'Connor PJ, Povey AC (1999) The relationship between 1,2-dimethylhydrazine dose and the induction of colon tumors: tumor development in female SWR mice does not require a K-ras mutational event. Carcinogenesis 20: 509–513. doi: 10.1093/carcin/20.3.509
[50]
Bhattacharyya S, Sul K, Krukovets I, Nestor C, Li J, et al.. (2012) Novel Tissue-Specific Mechanism of Regulation of Angiogenesis and Cancer Growth in Response to Hyperglycemia. J Am Heart Assoc.
[51]
Ito K, Ishigamori R, Mutoh M, Ohta T, Imai T, et al. (2013) Ay allele promotes azoxymethane-induced colorectal carcinogenesis by macrophage migration in hyperlipidemic/diabetic KK mice. Cancer Sci 104(7): 835–43. doi: 10.1111/cas.12162
[52]
Nathan DM, Lachin J, Cleary P, Orchard T, Brillon DJ, et al. (2003) Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med 348: 2294–2303. doi: 10.1056/nejmoa022314
[53]
Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, et al. (2005) Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353: 2643–2653. doi: 10.1056/nejmoa052187
[54]
Martin A, Komada MR, Sane DC (2003) Abnormal angiogenesis in diabetes mellitus. Med Res Rev 23: 117–145. doi: 10.1002/med.10024
[55]
Stenina OI (2005) Regulation of vascular genes by glucose. Curr Pharm Des 11: 2367–2381. doi: 10.2174/1381612054367283
[56]
Ferguson RD, Novosyadlyy R, Fierz Y, Alikhani N, Sun H, et al. (2012) Hyperinsulinemia enhances c-Myc-mediated mammary tumor development and advances metastatic progression to the lung in a mouse model of type 2 diabetes. Breast Cancer Res 14: R8. doi: 10.1186/bcr3089
[57]
Yabe Y, Kobayashi N, Nishihashi T, Takahashi R, Nishikawa M, et al. (2001) Prevention of neutrophil-mediated hepatic ischemia/reperfusion injury by superoxide dismutase and catalase derivatives. J Pharmacol Exp Ther 298: 894–899.
[58]
De Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, et al. (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18: 2938–2947.
[59]
Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, et al. (2000) Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18: 136–147.
[60]
Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K (2009) Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 69: 7507–7511. doi: 10.1158/0008-5472.can-09-2994
[61]
Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, et al. (2005) Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neutransgenic mice. Exp Gerontol 40: 685–693. doi: 10.1016/j.exger.2005.07.007
[62]
Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, et al. (2010) Metformin prevents tobacco carcinogen–induced lung tumorgenesis. Cancer Prev Res 3: 1066–1076. doi: 10.1158/1940-6207.capr-10-0055
[63]
Saito T, Chiba T, Yuki K, Zen Y, Oshima M, et al. (2013) Metformin, a Diabetes Drug, Eliminates Tumor-Initiating Hepatocellular Carcinoma Cells. Plos one 8: e70010. doi: 10.1371/journal.pone.0070010
[64]
Tomimoto A, Endo H, Sugiyama M, Fujisawa T, Hosono K, et al. (2008) Metformin suppresses intestinal polyp growth in ApcMin/+ mice. Cancer Sci 99: 2136–2141. doi: 10.1111/j.1349-7006.2008.00933.x
[65]
Hosono K, Endo H, Takahashi H, Sugiyama M, Uchiyama T, et al. (2010) Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase. Mol Carcinogenesis 49: 662–671. doi: 10.1002/mc.20637
[66]
Shank JJ, Yang K, Ghannam J, Cabrera L, Johnston CJ, et al. (2012) Metformin targets ovarian cancer stem cells in vitro and in vivo. Gynecol Oncol 127: 390–397. doi: 10.1016/j.ygyno.2012.07.115
[67]
Landman GW, Kleefstra N, Kornelis JJ, Groenier KH, Gans ROP, et al. (2009) the American Diabetes Association. Metformin Associated With Lower Cancer Mortality in Type 2 Diabetes. Diabetes care 33: 322–326. doi: 10.2337/dc09-1380
