Quercetin, Quercetrin Except Rutin Potentially Increased Pirarubicin Cytotoxicity by Non-Competitively Inhibiting the P-Glycoprotein-and MRP1 Function in Living K562/adr and GLC4/adr Cells

Problem statement: Quercetin and its glycoside derivatives are increasingly receiving interests as new generation of anticancer molecules and were recognized by multidrug resistant transporters such as P-glycoprotein and MRP1 protein. Of relevance to their use as anticancer agents alone or in combination with other agents, this study aims to analyze the interaction of the compounds with the MDR transporters including P-glycoprotein and MRP1 protein in living multidrug resistant cells. Approach: The potential MDR reversing action of flavonoids was assessed by using the co-treatment of anticancer drug, pirarubicin or daunorubicin and quercetin, quercetrin or rutin compared with the series of co-treatment of pirarubicin or daunorubicin and the known inhibitor such as cyclosporine A and verapamil. The evidence of direct interaction of molecules with MDR protein was investigated by measuring the ability of inhibition of the rate of P-glycoprotein- and MRP1-mediated efflux of pirarubicin out of cells. Results: Quercetin and its glycoside derivatives efficiently inhibited cancer cell proliferation and re-sensitize the MDR cells to pirarubicin but not for daunorubicin. Our results clearly show that quercetin, quercetrin except rutin non-competitively inhibited the function of P-glycoprotein in K562/adr and MRP1 in GLC4/adr cells. The determined KI value of P-glycoprotein was equal to 0.33 µM for quercetin and 1 µM for quercetrin and K_I value of MRP1 was equal to 0.45 µM for quercetin and 0.5 µM for quercetrin. Conclusion: The overall results demonstrated that quercetin, quercetrin and rutin should be considered as potential pharmaceutical molecules that might be used as MDR inhibitors.