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Experimental and Simulation Identification of Xanthohumol as an Inhibitor and Substrate of ABCB1

State Key Laboratory of Biological Fermentation Engineering of Beer, Qingdao 266061, China
Key Laboratory of Marine Bioactive Substance, The First Institute of Oceanography, State Oceanic Administration, Qingdao 266061, China
College of Science and Mathematics, Rowan University, Glassboro, NJ 08028, USA
Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh, Pittsburgh, PA 15232, USA
Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15232, USA
School of Foreign Language, Qufu Normal University, Qufu 273165, China
School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
Authors to whom correspondence should be addressed.
Appl. Sci. 2018, 8(5), 681;
Received: 30 March 2018 / Revised: 11 April 2018 / Accepted: 15 April 2018 / Published: 27 April 2018
(This article belongs to the Section Chemistry)
PDF [3020 KB, uploaded 3 May 2018]


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. View Full-Text
Keywords: xanthohumol; doxorubicin resistance; synergism; ABCB1 xanthohumol; doxorubicin resistance; synergism; ABCB1

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Liu, F.; Hoag, H.; Wu, C.; Liu, H.; Yin, H.; Dong, J.; Qian, Z.; Miao, F.; Liu, M.; Miao, J. Experimental and Simulation Identification of Xanthohumol as an Inhibitor and Substrate of ABCB1. Appl. Sci. 2018, 8, 681.

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