Abstract 2928: Metformin, an antidiabetic drug that modulates the AMPK/mTOR pathway, prevents tobacco carcinogen-induced lung tumorigenesis
Authors: Memmott Regan M. , Mercado Jose R. , Maier Colleen R. , Kawabata Shigeru , Fox Stephen D. , Dennis Phillip A. 
Published: February 2011

Abstract
Lung cancer is the leading cause of cancer-related death in the US, and new targets for the prevention or treatment of lung cancer are needed. The serine-threonine kinase mTOR is a potential candidate because it regulates cellular metabolism, growth, and proliferation. Exposure of A/J mice to the tobacco carcinogen NNK induces lung tumorigenesis that is dependent on mTOR because the mTOR inhibitor rapamycin prevents tumor growth by 90%. However, the clinical development of rapamycin may be limited due to toxicities, and identification of better-tolerated drugs that inhibit mTOR may lead to greater clinical application. One candidate is the biguanide metformin, which is widely prescribed for the treatment of type II diabetes, and long-term treatment causes few adverse effects. Metformin is an effective anti-diabetic agent because it activates AMPK, a master regulator of cell metabolism. Metformin might also be effective in the prevention of tobacco carcinogen-induced lung tumorigenesis because AMPK inhibits the mTOR pathway. A/J mice were fed a tumorigenic diet (AIN-93G/M) and treated with metformin in drinking water (1 or 5 mg/mL) for 13 wks following exposure to NNK. Metformin was well tolerated and reduced lung tumor burden in each treatment group by 40-50%. Plasma levels of metformin reached steady-state concentrations that are achievable in humans. Analysis of AMPK activation and mTOR inhibition in lung tumors showed that each biomarker was changed modestly. These data demonstrate that oral metformin inhibits NNK-induced lung tumorigenesis, but to a lesser extent than historical comparisons with rapamycin, suggesting that modest inhibition of mTOR resulted in less tumor inhibition. To test whether an intraperitoneal administration schedule might improve mTOR inhibition, we injected mice with metformin (250 mg/kg) for 3 days, and assessed biomarkers in liver and lung tissues. In liver tissue, metformin activated AMPK but did not inhibit mTOR. In lung tissue, metformin did not activate AMPK but did inhibit phosphorylation of IGF-IR, Akt, ERK, and mTOR. This suggests that metformin activated hepatic AMPK, which indirectly inhibited mTOR in lung tissue by decreasing levels of circulating insulin and/or IGF-I. Based on these data, we repeated the NNK-induced lung tumorigenesis study using intraperitoneal administration of metformin. Mice were treated for 13 wk with daily injections of metformin. Metformin was well tolerated and inhibited the development of fatty liver, which was observed in the control group fed the tumorigenic diet. Moreover, metformin decreased tumor burden by 72%, which correlated with decreased cellular proliferation and marked inhibition of mTOR in tumors. These studies show that metformin inhibits NNK-induced lung tumorigenesis, and support clinical testing of metformin as a chemopreventive agent.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2928.