The effect of clotrimazole on energy substrate uptake and carcinogenesis in intestinal epithelial cells.

Clotrimazole has anticarcinogenic activity in several cell types. Our aims were to investigate the anticarcinogenic effect of clotrimazole in a tumoral intestinal epithelial (Caco-2) cell line, to compare it with the effect in a nontumoral intestinal epithelial cell line (IEC-6 cells), and to investigate inhibition of energy substrate uptake as a mechanism contributing to it. The effect of clotrimazole on cell proliferation, viability and differentiation, H-deoxyglucose (H-DG), H-O-methyl-glucose (H-OMG), and C-butyrate uptake, as well as mRNA expression levels of glucose transporters was assessed. In Caco-2 cells, clotrimazole decreased cellular viability and proliferation and increased cell differentiation. The effect on cell proliferation and viability was potentiated by rhodamine123. Clotrimazole also decreased cellular viability and proliferation in IEC-6 cells, but increased the cellular DNA synthesis rate and had no effect on cell differentiation. Exposure of Caco-2 cells to clotrimazole (10 µmol/l) for 1 and 7 days increased (by 20-30%) the uptake of H-DG and H-OMG, respectively, but had no effect on C-butyrate uptake. The effect on H-DG and H-OMG transport was maximal at 10 µmol/l, and the pharmacological characteristics of transport were not changed. However, clotrimazole changed the mRNA expression levels of the facilitative glucose transporter 2 and the Na-dependent glucose cotransporter. Clotrimazole exhibits comparable cytotoxic effects in tumoral and nontumoral intestinal epithelial cell lines. In Caco-2 cells, the cytotoxic effect of clotrimazole was strongly potentiated by the inhibition of oxidative phosphorylation. Moreover, stimulation of glucose uptake might be a compensation mechanism in response to the glycolysis inhibition caused by clotrimazole.