HZ08 inhibits the multi-drug resistance on multiple sites as the substrate of p-glycoprotein
HZ08 inhibits the multi-drug resistance on multiple sites as the substrate of p-glycoprotein
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HZ08作为p-糖蛋白的底物，在多个位点上抑制多药耐药性。
DOI：
10.1016/j.ejphar.2013.04.028
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发表时间：
2013-07-15
影响因子：
5
通讯作者：
Huang, Wenlong
中科院分区：
文献类型：
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作者：
Feng, Yidong;Hu, Yahui;Huang, Wenlong
p-糖蛋白（p-gp）的过度表达导致多药耐药（MDR）的产生，这些耐药可释放多种结构异质性的抗肿瘤化学物质。HZ08是一种新型的四氢异喹啉衍生物，可以调节MDR。前期研究证实其对p-gp引起的多药耐药有明确的抑制作用，并能促进细胞内细胞毒素的积累。为了探究HZ08是否是p-gp的底物以及在哪些位点上发挥作用，我们引入了对mdr1的RNAi，并研究了HZ08与一些具有明确结合位点的经典药物（维拉帕米、罗达明123）的相互作用。实验结果表明，HZ08最可能是p-gp的底物，可能与维拉帕米具有相同的p-gp调制位点。得到的数据还表明罗丹明123与HZ08有一个共同的结合位点，但HZ08与阿霉素之间存在负竞争。综上所述，HZ08可能是p-gp的底物，并作为多靶点调制器逆转p-gp的外排函数。(C) 2013 Elsevier B.V.版权所有
Overexpression of p-glycoprotein (p-gp) leads to the production of multi-drug resistance (MDR) which could discharge various anti-tumor chemicals with structural heterogeneity. HZ08, a novel tetrahydroisoquinoline derivate, was discovered to modulate the MDR. What was confirmed is its definite inhibition of multi-drug resistance caused by p-gp and its promotion for the intracellular cytotoxins accumulation in the previous study. In order to explore whether HZ08 is the substrate of p-gp and on which sites it exerts its function, RNAi to mdr1 was introduced and the interaction between HZ08 and some classic agents (verapamil, rhodamine 123) with clearly binding sites was also investigated. Experimental results revealed that HZ08 is the most probable substrate of p-gp and may share the same modulation sites located at the p-gp with verapamil. Data obtained also indicated that there is a common binding site shared by rhodamine 123 and HZ08, but negative competition showed between HZ08 and adriamycin. In conclusion, HZ08 may be the substrate of p-gp and acts as a multiple target modulator to invert the efflux function of p-gp. (C) 2013 Elsevier B.V. All rights reserved.