Glabridin resensitizes p-glycoprotein-overexpressing multidrug-resistant cancer cells to conventional chemotherapeutic agents

Abstract

Multidrug resistance (MDR) remains an obstacle to chemotherapy related with the overexpression of several efflux membrane proteins, and p-glycoprotein (P-gp) is the most studied among them. Thus, continuous investigational efforts are necessary to find valuable MDR reversal agents, and the flavonoid compound glabridin (GBD) seems to be a promising candidate. This study aimed to investigate the potential of GBD against MDR and explore the possible mechanisms. First, we found that GBD could decrease the half maximal inhibitory concentration of paclitaxel and doxorubicin (DOX) in breast cancer cells like MDA-MB-231/MDR1 cells and MCF-7/ADR cells. It was further explained that GBD enhanced the apoptosis of MDA-MB-231/MDR1 cells induced by DOX, due to the increased accumulation of DOX. Then, tests were performed to explore the possible MDR reversal mechanisms. On one hand, GBD can suppress the expression of P-gp. On the other hand, GBD can downregulate the activity of P-gp ATPase when cotreated with DOX or verapamil, revealing that GBD was a substrate of P-gp. Moreover, the obtained kinetic inhibition parameters proved that GBD was a competitive inhibitor of P-gp, and in molecular docking simulation modeling, GBD exhibited stronger binding affinity with P-gp than DOX. In conclusion, GBD can increase the accumulation of DOX in MDA-MB-231/MDR1 cells by suppressing the expression of P-gp and competitively inhibiting the P-gp efflux pump and enhance the apoptosis of MDA-MB-231/MDR1 cells induced by DOX, and thus realize reversal effects on MDR. Therefore, the combination therapy of anticancer drugs and flavonoid-like GBD is a promising strategy to overcome P-gp-mediated MDR.