YHHU0895, a novel synthetic small-molecule microtubule-destabilizing agent, effectively overcomes P-glycoprotein-mediated tumor multidrug resistance
YHHU0895, a novel synthetic small-molecule microtubule-destabilizing agent, effectively overcomes P-glycoprotein-mediated tumor multidrug resistance
复制标题
YHHU0895是一种新型合成小分子微管去稳定剂，有效克服P-糖蛋白介导的肿瘤多药耐药性
DOI：
10.1016/j.canlet.2011.09.013
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发表时间：
2012-01-01
期刊：
影响因子：
9.7
通讯作者：
Lou, Liguang
中科院分区：
文献类型：
--
作者：
Zhao, Hongbing;Quan, Haitian;Lou, Liguang
P-糖蛋白介导的多药耐药（MDR）是大多数微管靶向药物疗效的主要限制因素。在这里，我们研究了新的，合成的，小分子微管不稳定剂，2-（2-氨基-5-（1-乙基-1H-吲哚-5-基）嘧啶-4-基）苯酚（YHHU 0895），其抗肿瘤活性和克服P-糖蛋白介导的MDR的潜力。YHHU 0895通过在秋水仙素结合位点与微管蛋白结合来抑制纯化的微管蛋白聚合，并显著抑制人肿瘤细胞增殖。值得注意的是，P-糖蛋白过表达的KBV 200和K562/ADR细胞，这是强烈耐药的秋水仙碱，长春瑞滨和紫杉醇，是敏感的YHHU 0895在体外和体内。这些发现表明YHHU 0895是一种新型的微管去稳定剂，具有治疗P-糖蛋白介导的耐药患者的潜力。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
P-glycoprotein-mediated multidrug resistance (MDR) is a major limiting factor in the efficacy of most microtubule-targeting agents. Here, we investigated the novel, synthetic, and small-molecule microtubule-destabilizing agent, 2-(2-amino-5-(1-ethyl-1H-indol-5-yl) pyrimidin-4-yl) phenol (YHHU0895), for its anti-tumor activity and potential for overcoming P-glycoprotein-mediated MDR. YHHU0895 inhibited purified tubulin polymerization through binding to tubulin at the colchicine-binding site and significantly inhibited human tumor cell proliferation. Notably, P-glycoprotein-overexpressing KBV200 and K562/ADR cells, which are strongly resistant to colchicine, vinorelbine and paclitaxel, were sensitive to YHHU0895 both in vitro and in vivo. These findings indicate that YHHU0895 is a novel type of microtubule-destabilizing agent that has the potential for the treatment of patients with drug resistance mediated by P-glycoprotein. (C) 2011 Elsevier Ireland Ltd. All rights reserved.