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

Gonçalves, Pedro; Gregório, Inês; Araújo, João R.; Martel, Fátima

doi: 10.1097/CAD.0b013e32834d9ad2

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, 3H-deoxyglucose (3H-DG), 3H-O-methyl-glucose (3H-OMG), and 14C-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 3H-DG and 3H-OMG, respectively, but had no effect on 14C-butyrate uptake. The effect on 3H-DG and 3H-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.

Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Porto, Portugal

Correspondence to Fátima Martel, Department of Biochemistry, Faculty of Medicine of Porto, Porto 4200-319, Portugal Tel: +351 22 5513624; fax: +351 22 5513624; e-mail:

Received June 13, 2011

Accepted September 28, 2011

© 2012 Lippincott Williams & Wilkins, Inc.