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

Liu, Fangming and Hoag, Hannah and Wu, Chun and Liu, Haizhou and Yin, Hua and Dong, Jianjun and Qian, Zhonghua and Miao, Feng and Liu, Ming and Miao, Jinlai (2018) Experimental and Simulation Identification of Xanthohumol as an Inhibitor and Substrate of ABCB1. Applied Sciences, 8 (5). p. 681. ISSN 2076-3417

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Liu, Fangming
Hoag, Hannah
Wu, Chun
Liu, Haizhouhal58@pitt.eduhal58
Yin, Hua
Dong, Jianjun
Qian, Zhonghua
Miao, Feng
Liu, Ming
Miao, Jinlai
Centers: Other Centers, Institutes, Offices, or Units > Pittsburgh Cancer Institute
Date: 27 April 2018
Date Type: Publication
Journal or Publication Title: Applied Sciences
Volume: 8
Number: 5
Publisher: MDPI AG
Page Range: p. 681
DOI or Unique Handle: 10.3390/app8050681
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
Uncontrolled Keywords: xanthohumol, doxorubicin resistance, synergism, ABCB1
ISSN: 2076-3417
Official URL:
Funders: Natural Science Foundation of China, Key Research and Development Program of Shandong Province, Natural Science Foundation of China-Shandong Joint Fund, Open Research Fund of State Key Laboratory of Biological Fermentation Engineering of Beer
Article Type: Research Article
Date Deposited: 19 May 2021 18:12
Last Modified: 19 May 2021 18:12


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