Selective inhibition of P-gp transporter by goniothalamin derivatives sensitizes resistant cancer cells to chemotherapy

Overexpression of efflux transporters of the ATP-binding cassette (ABC) transporter family, primarily P-glycoprotein (P-gp), is a frequent cause of multidrug resistance in cancer and leads to failure of current chemotherapies. Thus, identification of selective P-gp inhibitors might provide a basis for the development of novel anticancer drug candidates. The natural product goniothalamin and 21 derivatives were characterized regarding their ability to inhibit ABC transporter function. Among the goniothalamins, selective inhibitors of P-gp were discovered. The two most potent inhibitors (R)-3 and (S)-3 displayed the ability to increase intracellular accumulation of doxorubicin, thereby sensitizing P-gp-overexpressing tumor cells to chemotherapy by decreasing doxorubicin IC50 value up to 15-fold. Molecular docking studies indicated these compounds to inhibit P-gp by acting as transporter substrates. In conclusion, our findings revealed a novel role of goniothalamin derivatives in reversing P-gp-mediated chemotherapy resistance.