Hydroxygenkwanin Improves the Efficacy of Cytotoxic Drugs in ABCG2-Overexpressing Multidrug-Resistant Cancer Cells

Yan Qing Li, Megumi Murakami, Yang Hui Huang, Tai Ho Hung, Shun Ping Wang, Yu Shan Wu, Suresh V. Ambudkar*, Chung Pu Wu*

*此作品的通信作者

研究成果: 期刊稿件文章同行評審

1 引文 斯高帕斯(Scopus)

摘要

Hydroxygenkwanin, a flavonoid isolated from the leaves of the Daphne genkwa plant, is known to have pharmacological properties; however, its modulatory effect on multidrug resistance, which is (MDR) mediated by ATP-binding cassette (ABC) drug transporters, has not been investigated. In this study, we examine the interaction between hydroxygenkwanin, ABCB1, and ABCG2, which are two of the most well-characterized ABC transporters known to contribute to clinical MDR in cancer patients. Hydroxygenkwanin is not an efflux substrate of either ABCB1 or ABCG2. We discovered that, in a concentration-dependent manner, hydroxygenkwanin significantly reverses ABCG2-mediated resistance to multiple cytotoxic anticancer drugs in ABCG2-overexpressing multidrug-resistant cancer cells. Although it inhibited the drug transport function of ABCG2, it had no significant effect on the protein expression of this transporter in cancer cells. Experimental data showing that hydroxygenkwanin stimulates the ATPase activity of ABCG2, and in silico docking analysis of hydroxygenkwanin binding to the inward-open conformation of human ABCG2, further indicate that hydroxygenkwanin sensitizes ABCG2-overexpressing cancer cells by binding to the substrate-binding pocket of ABCG2 and attenuating the transport function of ABCG2. This study demonstrates the potential use of hydroxygenkwanin as an effective inhibitor of ABCG2 in drug combination therapy trials for patients with tumors expressing higher levels of ABCG2.

原文英語
文章編號12763
期刊International Journal of Molecular Sciences
23
發行號21
DOIs
出版狀態已出版 - 11 2022

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