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.
KeywordsGoniothalamin Multidrug resistance P-glycoprotein Cancer chemotherapy Resistance reversal
Breast cancer resistance protein
Multidrug resistance-associated protein 1
We would like to thank Dr. Erasmus Schneider (Wadsworth Center, New York State Department of Health, Albany, NY, USA) for kindly providing the MCF-7/MX cells.
This work was funded by the German Federal Ministry for Economic Affairs and Energy (‘ZIM Kooperationsprojekt’ KF3279X01AJ3) and A.W. was supported by a scholarship of the Studienstiftung des deutschen Volkes. The PhD training of J.S. was financed by the graduate program in Pharmacology and Experimental Therapeutics at the University of Cologne, which is financially and scientifically supported by Bayer.
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Conflict of interests
The authors declare that they have no conflict of interest.