ced Lung Tumorigenesis

r Prev Res vation of the mammalian target of rapamycin (mTOR) pathway is an important and early event in o carcinogen–induced lung tumorigenesis, and therapies that target mTOR could be effective in the tion or treatment of lung cancer. The biguanide metformin, which is widely prescribed for the ent of type II diabetes, might be a good candidate for lung cancer chemoprevention because it tes AMP-activated protein kinase (AMPK), which can inhibit the mTOR pathway. To test this, A/J ere treated with oral metformin after exposure to the tobacco carcinogen 4-(methylnitrosamino)yridyl)-1-butanone (NNK). Metformin reduced lung tumor burden by up to 53% at steady-state a concentrations that are achievable in humans. mTOR was inhibited in lung tumors but only stly. To test whether intraperitoneal administration of metformin might improve mTOR inhibition, jected mice and assessed biomarkers in liver and lung tissues. Plasma levels of metformin were cantly higher after injection than oral administration. In liver tissue, metformin activated AMPK hibited mTOR. In lung tissue, metformin did not activate AMPK but inhibited phosphorylation ulin-like growth factor-I receptor/insulin receptor (IGF-1R/IR), Akt, extracellular signal–regulated (ERK), and mTOR. This suggested that metformin indirectly inhibited mTOR in lung tissue by sing activation of insulin-like growth factor-I receptor/insulin receptor and Akt upstream of mTOR. on these data, we repeated the NNK–induced lung tumorigenesis study using intraperitoneal istration of metformin. Metformin decreased tumor burden by 72%, which correlated with sed cellular proliferation and marked inhibition of mTOR in tumors. These studies show that decrea metformin prevents tobacco carcinogen–induced lung tumorigenesis and support clinical testing of metformin as a chemopreventive agent. Cancer Prev Res; 3(9); 1066–76. ©2010 AACR.