Modulation of P-glycoprotein, cytochrome P450, and glutathione-S-transferase by resveratrol in human cancer cells

Abstract

Resistance of cancer cells to chemotherapy is controlled by a decrease of intracellular drug accumulation, increase of detoxification, and diminished propensity of cancer cells to undergo apoptosis. ABC-membrane transporters together with intracellular metabolic enzymes contribute to the complex and unresolved phenomenon of multidrug resistance (MDR). Resveratrol, a polyphenol of Fallopia japonica (Houtt.) Ronse Decr., has antiinflammatory and antioxidant properties [1]. However, it is also interesting in the field of cancer therapy [2]. The mechanisms by which resveratrol might produce anticancer effects are not well understood. In this study, resveratrol was shown to increase Rho123 and calcein accumulation in a concentration dependent manner (1–500µM) in Caco-2 cells by 3–167% and 5–361% of verapamil. Morever, the treatment of CEM/ADR5000 with 10–100µM resveratrol significantly inhibited the Rho123 and calcein efflux by 107–407%, and 164–460% as compared with verapamil (100%), respectively. The cytotoxicity of doxorubicin was enhanced by using 20µM resveratrol; IC50 values were decreased from 4.15 to 1.23µM, and from 33.67 to 1.81µM, respectively. Furthermore, resveratrol significantly inhibited GST and cytochrome P450 enzyme activity in a dose dependent manner with IC50 values 33.30µM and 11.49µM, respectively. RT-PCR reveals a significantly down-regulation of ABC-transporters and of smetabolic enzymes mRNA levels in Caco-2 cell lines in response to resveratrol treatment. In conclusion, the inhibition of both ABC-transporters and of metabolic enzymes could explain the advantages of resveratrol in cancer therapy.