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题名: BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe
作者: Bai, Zhaoshi1;  Gao, Meiqi1;  Zhang, Huijuan1;  Guan, Qi2;  Xu, Jingwen1;  Li, Yao1;  Qi, Huan3;  Li, Zhengqiang1;  Zuo, Daiying1;  Zhang, Weige2;  Wu, Yingliang1
关键词: CBSIs ;  Multidrug resistance ;  P-glycoprotein ;  Apoptosis-resistance ;  Mitotic catastrophe
刊名: CANCER LETTERS
发表日期: 2017-08-28
DOI: 10.1016/j.canlet.2017.05.016
卷: 402, 页:81-92
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Oncology
研究领域[WOS]: Oncology
英文摘要: Multidrug resistance (MDR) interferes with the efficiency of chemotherapy. Therefore, developing novel anti-cancer agents that can overcome MDR is necessary. Here, we screened a series of colchicine binding site inhibitors (CBSIs) and found that 5-(3, 4, 5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) displayed potent cytotoxic activity against both A549 and A549/Taxol cells. We further explored the underlying mechanisms and found that BZML caused mitosis phase arrest by inhibiting tubulin polymerization in A549 and A549/Taxol cells. Importantly, BZML was a poor substrate for P-glycoprotein (P-gp) and inhibited P-gp function by decreasing P-gp expression at the protein and mRNA levels. Cell morphology changes and the expression of cycle- or apoptosis-related proteins indicated that BZML mainly drove A549/Taxol cells to die by mitotic catastrophe (MC), a p53-independent apoptotic-like cell death, whereas induced A549 cells to die by apoptosis. Taken together, our data suggest that BZML is a novel colchicine binding site inhibitor and overcomes MDR in A549/Taxol cells by inhibiting P-gp function and inducing MC. Our study also offers a new strategy to solve the problem of apoptosis-resistance. (C) 2017 Elsevier B.V. All rights reserved.
关键词[WOS]: BREAST-CANCER CELLS ;  LUNG-CANCER ;  MICROTUBULE INHIBITOR ;  ANTITUMOR-ACTIVITY ;  DRUG-RESISTANCE ;  IN-VITRO ;  TUBULIN ;  GLYCOPROTEIN ;  MECHANISMS ;  APOPTOSIS
语种: 英语
WOS记录号: WOS:000406168800009
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/152036
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Shenyang Pharmaceut Univ, Dept Pharmacol, 103 Wenhua Rd, Shenyang 110016, Liaoning, Peoples R China
2.Shenyang Pharmaceut Univ, Minist Educ, Key Lab Struct Based Drug Design & Discovery, 103 Wenhua Rd, Shenyang 110016, Liaoning, Peoples R China
3.Chinese Acad Sci, Dalian Inst Chem Phys, Sci Res Ctr Translat Med, Dalian 116023, Peoples R China

Recommended Citation:
Bai, Zhaoshi,Gao, Meiqi,Zhang, Huijuan,et al. BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe[J]. CANCER LETTERS,2017,402:81-92.
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