Abstract 2272: Comparison of metformin, pheformin and buformin in mammary carcinogenesis in non-obese, non-diabetic rats.

Abstract

Abstract Emerging evidence from studies of human pharmacoepidemiology indicate that metformin, an antidiabetic drug, is associated with reduced breast cancer risk in diabetic individuals. Data from preclinical mammary carcinogenesis studies in the rat indicate that metformin also has protective activity against chemically-induced mammary cancer in non diabetic rats, but the dose required for inhibition is above that used clinically for the treatment of diabetes. Human breast cancer cell growth also is inhibited by metformin, but at concentrations far in excess of anti-diabetic plasma concentrations of the drug. It is likely that pharmacokinetic/pharmacodyanmic factors contribute to this blunted sensitivity, possibly due to carcinogenesis-associated down regulation of organic cationic transporters (OCT) required for cellular uptake of metformin. Since some biguanides such as phenformin and buformin are not dependent on OCT for cellular accumulation, their effects against mammary carcinogenesis were evaluated in comparison to metformin as a proof-in-concept study that could set the stage for development of second generation biguanides. The hypothesis evaluated was that inhibition of mammary carcinogenesis by phenformin and buformin would be superior to metformin. Female Sprague Dawley rats (n=30/group) were injected with 1-methyl-1-nitrosourea (50 mg/kg) at 21 days of age and 7 days thereafter randomized to metformin, phenformin or buformin dietary groups and fed respective biguanides (10 mmol/kg) diets for 6 weeks. Both phenformin and buformin significantly reduced the number of mammary adenocarcinoma per rat (3.6, 1.6, and 0.7 cancers/rat for metformin, phenformin and buformin respectively) and tumor burden (1.61, 0.63, and 0.12 g/rat for metformin, phenformin and buformin respectively) and elongated cancer latency compared to metformin (40, 45, and 48 days post carcinogen for metformin, phenformin and buformin respectively) (p<0.05). Mammary cancer incidence was also lower in animals fed phenformin (77%) or buformin (43%) diet vs metformin (93%), but the difference was only significant between metformin and buformin (p<0.001). Cell culture experiments confirmed the carcinogenesis data. The comparative effects of these biguanides on the LKB1/AMPK axis will be reported. The associated mechanisms of cell growth inhibiton are under investigation. Supported by PHS grant CA52626 from the National Cancer Institute. Citation Format: Zongjian Zhu, Weiqin Jiang, John N. McGinley, Henry J. Thompson. Comparison of metformin, pheformin and buformin in mammary carcinogenesis in non-obese, non-diabetic rats. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2272. doi:10.1158/1538-7445.AM2013-2272