Morellic Acid B Overcomes <i>P</i>-Glycoprotein-Mediated Multidrug Resistance in Hepatocellular Carcinoma Cells via Regulation of MAPK/NF-kB Signaling Pathways

Multidrug resistance (MDR) is a major clinical obstacle to chemotherapy. The discovery of promising MDR sensitizers is now focused on new, nontoxic, and more efficient <i>P</i>-glycoprotein (P-gp) inhibitors from natural products. In this study, we investigated the MDR-reversing effects of morellic acid B (MAB), a xanthonoid isolated from gamboge, in the doxorubicin (DOX)-resistant human hepatoma cell line BEL-7402/Adr with verapamil as a positive control. Moreover, the function and expression of P-gp, as well as the anti-MDR mechanism, were explored. MAB antagonized the resistance and boosted the cell apoptosis induced by DOX significantly in BEL-7402/Adr cells compared to sensitive cells. Increased intracellular accumulation of DOX and rhodamine 123 by MAB indicated that MAB inhibited the efflux mediated by P-gp. Notably, we found that MAB markedly reduced the expression of P-gp in a concentration-dependent manner in the resistance BEL-7402/Adr cells, but not for sensitive BEL-7402 cells. Moreover, MAB inhibited the NF-κB and phosphorylation of P-p38 MAPK expressions. Collectively, MAB overcomes the P-gp-mediated drug resistance to DOX in B-7402/Adr by inhibiting the function and expression of P-gp, which may relate to its modulating effects on the NF-κB and p38 MAPK signaling pathways. Suggests that MAB has the potential to be a reversal agent for overcoming drug-resistant tumors.