Document Type

Article

Version Deposited

Published Version

Publication Date

4-27-2018

Publication Title

Applied Sciences

DOI

10.3390/app8050681

Abstract

Xanthohumol (XN) is a well-known prenylated flavonoid found in Humulus lupulus L. It is involved in several pharmacological activities, including the sensitization of doxorubicin-resistant breast cancer (MCF-7/ADR) cells to doxorubicin (DOX) through a reduction in cell viability and stemness. In the present study, we revealed another mechanism to further explain the reverse of the drug resistance of XN. In the MCF-7/ADR cell line, we found that XN inhibited the efflux functions of ATP-binding cassette subfamily B member 1 (ABCB1). We also observed that XN was a substrate of ABCB1 and stimulated its ATPase activity. Moreover, our results revealed that XN showed a synergic effect with the ABCB1 substrate colchicine (COL) in the MCF-7/ADR cell line. Further, we showed that XN bound to the central transmembrane domain (TMD) site, overlapping with the DOX binding site. This mechanism was supported by molecular modeling and simulation data, which revealed that XN bound to the ABCB1 transmembrane domain, where doxorubicin also binds, and its binding affinity was stronger than that of doxorubicin, resulting in less protein and ligand position fluctuation. These results support the XN-induced reversal of drug resistance via the inhibition of ABCB1-mediated transport of doxorubicin, stimulating ABCB1 ATPase activity and acting as a substrate of ABCB1.

Comments

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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