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BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe
Bai, Zhaoshi1; Gao, Meiqi1; Zhang, Huijuan1; Guan, Qi2; Xu, Jingwen1; Li, Yao1; Qi, Huan3; Li, Zhengqiang1; Zuo, Daiying1; Zhang, Weige2; Wu, Yingliang1
KeywordCbsis Multidrug Resistance P-glycoprotein Apoptosis-resistance Mitotic Catastrophe
Source PublicationCANCER LETTERS
2017-08-28
DOI10.1016/j.canlet.2017.05.016
Volume402Pages:81-92
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
WOS SubjectOncology
WOS Research AreaOncology
WOS KeywordBREAST-CANCER CELLS ; LUNG-CANCER ; MICROTUBULE INHIBITOR ; ANTITUMOR-ACTIVITY ; DRUG-RESISTANCE ; IN-VITRO ; TUBULIN ; GLYCOPROTEIN ; MECHANISMS ; APOPTOSIS
AbstractMultidrug 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.
Language英语
WOS IDWOS:000406168800009
Citation statistics
Cited Times:7[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/152036
Collection中国科学院大连化学物理研究所
Affiliation1.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
GB/T 7714
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.
APA Bai, Zhaoshi.,Gao, Meiqi.,Zhang, Huijuan.,Guan, Qi.,Xu, Jingwen.,...&Wu, Yingliang.(2017).BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe.CANCER LETTERS,402,81-92.
MLA Bai, Zhaoshi,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".CANCER LETTERS 402(2017):81-92.
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