Abstract
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 KI value of MRP1 was equal to 0.45 mM for quercetin and 0.5 mM 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.
Highlights
Bioflavonoids such as quercetin, apigenin and kaempferol are increasingly receiving interests as new generation of anticancer molecules due to their antioxidant and cancer apoptosis induction activity (Kothan et al, 2004; Dechsupa et al, 2007; Galati and O'Brien, 2004; Jeong et al, 2009; Tan and Swain, 2002)
Quercetin, quercetrin and rutin exhibited antiproliferation in K562, K562/adr, GLC4 and GLC4/adr cells; the IC50 values were in micromolar range
It should be noted that pirarubicin is very high efficacy in K562 and GLC4 (IC50 is about 7±2 nM) but it was recognized and pumped out from K562/adr cells by P-glycoprotein and from GLC4/adr by MRP1 protein
Summary
Bioflavonoids such as quercetin, apigenin and kaempferol are increasingly receiving interests as new generation of anticancer molecules due to their antioxidant and cancer apoptosis induction activity (Kothan et al, 2004; Dechsupa et al, 2007; Galati and O'Brien, 2004; Jeong et al, 2009; Tan and Swain, 2002). These researchers made evidence that how an antioxidant molecule could be potentially anticancer molecule of both in vitro studies using cells and in vivo studies using rat bearing cancer tissue as models. The particular interests are these flavonoids mediated almost the same antiproliferation efficacy in multidrug-resistant cancer cells such as K562/adr which over-expressed P-glycoprotein and GLC4/adr which over-expressed MRP1 protein when compared with their corresponding drug-sensitive cells (Tungjai et al, 2008)
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