BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe
BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe
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BZML 是一种新型秋水仙碱结合位点抑制剂，通过抑制 P-gp 功能和诱导有丝分裂灾难来克服 A549/Taxol 细胞的多药耐药性
DOI：
10.1016/j.canlet.2017.05.016
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发表时间：
2017-08-28
期刊：
影响因子：
9.7
通讯作者：
Wu, Yingliang
中科院分区：
文献类型：
--
作者：
Bai, Zhaoshi;Gao, Meiqi;Wu, Yingliang
多药耐药性（MDR）会干扰化疗的效率。因此，开发能够克服MDR的新型抗癌药物是必要的。在这里，我们筛选了一系列秋水仙碱结合位点抑制剂（CBSI），发现5-(3,4,5-三甲氧基苯甲酰基)-4-甲基-2-(对甲苯基)咪唑(BZML)对A549和A549/紫杉醇细胞均表现出有效的细胞毒活性。我们进一步探讨了潜在的机制，发现 BZML 通过抑制 A549 和 A549/Taxol 细胞中的微管蛋白聚合而导致有丝分裂期停滞。重要的是，BZML 是 P-糖蛋白 (P-gp) 的不良底物，并通过降低蛋白质和 mRNA 水平的 P-gp 表达来抑制 P-gp 功能。细胞形态的变化以及周期或凋亡相关蛋白的表达表明，BZML主要驱动A549/Taxol细胞通过有丝分裂灾难(MC)死亡，这是一种不依赖于p53的细胞凋亡样细胞死亡，而诱导A549细胞通过凋亡死亡。综上所述，我们的数据表明 BZML 是一种新型秋水仙碱结合位点抑制剂，通过抑制 P-gp 功能和诱导 MC 来克服 A549/Taxol 细胞中的 MDR。我们的研究还为解决细胞凋亡抵抗问题提供了新策略。 (C) 2017 Elsevier B.V. 保留所有权利。
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.