TY - JOUR
T1 - Experimental and simulation identification of xanthohumol as an inhibitor and substrate of ABCB1
AU - Liu, Fangming
AU - Hoag, Hannah
AU - Wu, Chun
AU - Liu, Haizhou
AU - Yin, Hua
AU - Dong, Jianjun
AU - Qian, Zhonghua
AU - Miao, Feng
AU - Liu, Ming
AU - Miao, Jinlai
N1 - Funding Information:
Acknowledgments: This work was funded by the Natural Science Foundation of China (No. 41576187), Key Research and Development Program of Shandong Province (No. 2016YYSP017, 2016ZDJS06A03, 2017GHY15112), Natural Science Foundation of China-Shandong Joint Fund (No. U1606403), and Open Research Fund of State Key Laboratory of Biological Fermentation Engineering of Beer (No. K2014002). We also acknowledge the High Performance Computing Facility at Rowan, funded by the National Science Foundation under the Grant MRI-1429467 and XSEDE MCB160164/160173/170088. The Anton2 machine at the Pittsburgh Supercomputing Center (PSCA17017P) was generously made available by D. E. Shaw Research.
Funding Information:
This work was funded by the Natural Science Foundation of China (No. 41576187), Key Research and Development Program of Shandong Province (No. 2016YYSP017, 2016ZDJS06A03, 2017GHY15112), Natural Science Foundation of China-Shandong Joint Fund (No. U1606403), and Open Research Fund of State Key Laboratory of Biological Fermentation Engineering of Beer (No. K2014002). We also acknowledge the High Performance Computing Facility at Rowan, funded by the National Science Foundation under the Grant MRI-1429467 and XSEDE MCB160164/160173/170088. The Anton2 machine at the Pittsburgh Supercomputing Center (PSCA17017P) was generously made available by D. E. Shaw Research.
Publisher Copyright:
© 2018 by the authors.
PY - 2018/4/27
Y1 - 2018/4/27
N2 - 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.
AB - 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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U2 - 10.3390/app8050681
DO - 10.3390/app8050681
M3 - Article
AN - SCOPUS:85046128623
VL - 8
JO - Applied Sciences (Switzerland)
JF - Applied Sciences (Switzerland)
SN - 2076-3417
IS - 5
M1 - 681
ER -