Effects of metformin and glibenclamide on insulin receptors in fibroblasts and tumor cells in vitro.

The effects of the oral hypoglycemic agents metformin and glibenclamide on receptor binding of insulin and insulin-induced receptor down-regulation were studied in cultured normal human fibroblasts, human breast tumors (cell lines MCF-7 and T-47D) and a human colon tumor (cell line HCT-8) in order to identify differences in receptor regulation between normal and transformed cells. Binding of 125I-insulin was not significantly altered in any cell type following 24-h exposure of cells to concentrations of these agents equivalent to the in vivo therapeutic range, either in the presence or absence of insulin. Glibenclamide (2 microM) and metformin (1-10 microM) induced a 13-28% reduction in insulin receptor down regulation in fibroblasts exposed to 1.7 x 10(-8)M-insulin, the loss of binding on exposure to insulin decreasing from 55% to 40-48%. Both agents induced a smaller percentage reduction in insulin-induced receptor down-regulation in HCT-8 cells exposed to 1.7 x 10(-8)M insulin for 4 h (26% binding loss reducing to 14-20% in the presence of drug) and in MCF-7 and T-47D cells exposed to 1.7 x 10(-7)M insulin for 4h (16% binding loss reducing to 10%). It remains to be shown whether these small differences in sensitivity of receptors in malignant and normal cells to regulation by insulin and oral hypoglycemic agents can be exploited clinically in cancer management programs.