The impact of type 2 diabetes and antidiabetic drugs on cancer cell growth.

Despite investigations into mechanisms linking type 2 diabetes and cancer, there is a gap in knowledge about pharmacotherapy for diabetes in cancer patients. Epidemiological studies have shown that diabetic cancer patients on different antidiabetic treatments have different survival. The clinically relevant question is whether some antidiabetic pharmacotherapeutic agents promote cancer whereas others inhibit cancer progression. We investigated the hypothesis that various antidiabetic drugs had differential direct impact on cancer cells using four human cell lines (pancreatic cancer: MiaPaCa2, Panc-1; breast cancer: MCF7, HER18). We found that insulin and glucose promoted cancer cell proliferation and contributed to chemoresistance. Metformin and rosiglitazone suppressed cancer cell growth and induced apoptosis. Both drugs affected signalling in the protein kinases B (AKT)/mammalian target of rapamycin pathway; metformin activated adenosine monophosphate (AMP)-activated protein kinase whereas rosiglitazone increased chromosome ten level. Although high insulin and glucose concentrations promoted chemoresistance, the combination of metformin or rosiglitazone with gemcitabine or doxorubicin, resulted in an additional decrease in live cancer cells and increase in apoptosis. In contrast, exenatide did not have direct effect on cancer cells. In conclusion, different types of antidiabetic pharmacotherapy had a differential direct impact on cancer cells. This study provides experimental evidence to support further investigation of metformin and rosiglitazone as first-line therapies for type 2 diabetes in cancer patients.