Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth

We investigated the effects of metformin on the growth of lewis lung LLC1 carcinoma in C57BL/6J mice provided with either a control diet or a high-energy diet, previously reported to lead to weight gain and systemic insulin resistance with hyperinsulinemia. Forty-eight male mice were randomized into four groups: control diet, control diet+metformin, high-energy diet, or high-energy diet+metformin. Following 8 weeks on the experimental diets, selected groups received metformin in their drinking water. Three weeks following the start of metformin treatment, mice were injected with 0.5x10(6) LLC1 cells and tumor growth was measured for 17 days. By day 17, tumors of mice on the high-energy diet were nearly twice the volume of those of mice on the control diet. This effect of diet on tumor growth was significantly attenuated by metformin, but metformin had no effect on tumor growth of the mice on the control diet. Metformin attenuated the increased insulin receptor activation associated with the high-energy diet and also led to increased phosphorylation of AMP kinase, two actions that would be expected to decrease neoplastic proliferation. These experimental results are consistent with prior hypothesis-generating epidemiological studies that suggest that metformin may reduce cancer risk and improve cancer prognosis. Finally, these results contribute to the rationale for evaluation of the anti-neoplastic activity of metformin in hyperinsulinemic cancer patients.