Liu Ming, Zhang Weiyi, Zhang Wei, Zhou Xin, Li Ming, Miao Jinlai
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China.
Toxins (Basel). 2017 Jun 30;9(7):208. doi: 10.3390/toxins9070208.
Isoxanthohumol is a unique prenylflavonoid with the highest content in beer. Isoxanthohumol has multiple bioactivities and has recently received considerable attention in the scientific community. Nonetheless; its effect on drug resistant cancer cells has rarely been studied. In this paper; we investigated the synergistic effect of isoxanthohumol and doxorubicin on doxorubicin resistant MCF-7/ADR cells. Our results showed that isoxanthohumol sensitized the cytotoxic effect of doxorubicin on MCF-7/ADR cells via increased proliferation inhibition and apoptosis stimulation. Molecular mechanism studies further demonstrated that isoxanthohumol inhibited ABCB1-mediated doxorubicin efflux; stimulated the ATPase activity of ABCB1 (ATP-binding cassette sub-family B member 1); and acted as an ABCB1 substrate. Molecular docking results suggested that isoxanthohumol bound to the central transmembrane domain of ABCB1 and its binding site overlapped with the doxorubicin binding site. The present studies demonstrated that isoxanthohumol was a competitive ABCB1 inhibitor which reversed ABCB1-mediated doxorubicin resistance in MCF-7/ADR cells; and therefore could be further developed to help with overcoming ABCB1-mediated drug resistance.
异黄腐酚是一种独特的异戊烯基黄酮类化合物，在啤酒中含量最高。异黄腐酚具有多种生物活性，最近在科学界受到了相当大的关注。尽管如此，其对耐药癌细胞的作用却鲜有研究。在本文中，我们研究了异黄腐酚和阿霉素对阿霉素耐药的MCF-7/ADR细胞的协同作用。我们的结果表明，异黄腐酚通过增强增殖抑制和促进凋亡，使阿霉素对MCF-7/ADR细胞的细胞毒性作用敏感化。分子机制研究进一步证明，异黄腐酚抑制ABCB1介导的阿霉素外排，刺激ABCB1（ATP结合盒亚家族B成员1）的ATP酶活性，并作为ABCB1的底物。分子对接结果表明，异黄腐酚与ABCB1的中央跨膜结构域结合，其结合位点与阿霉素的结合位点重叠。本研究表明，异黄腐酚是一种竞争性ABCB1抑制剂，可逆转ABCB1介导的MCF-7/ADR细胞对阿霉素的耐药性，因此可进一步开发用于克服ABCB1介导的耐药性。
