BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe. (28th August 2017)

• Record Type: Journal Article
• Authors: Bai, Zhaoshi; Gao, Meiqi; Zhang, Huijuan; Guan, Qi; Xu, Jingwen; Li, Yao; Qi, Huan; Li, Zhengqiang; Zuo, Daiying; Zhang, Weige; Wu, Yingliang
• Is Part Of: Cancer letters. Volume 402(2017)
• Page Start: 81
• Page End: 92
• Publication Date: 2017-08-28
• Subjects: CBSIs -- Multidrug resistance -- P-glycoprotein -- Apoptosis-resistance -- Mitotic catastrophe; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.05.016
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: BZML, as a novel CBSIs, has broad spectrum cytotoxic activity against various chemo-sensitive or -resistant cancer cells. BZML is not a P-gp substrate and acts as an irreversible inhibitor of P-gp function in A549/Taxol cells. BZML causes mitosis phase arrest by inhibiting tubulin polymerization in A549 and A549/Taxol cells. BZML induces MC in A549/Taxol cells, which is different from apoptosis in A549 cells, to against apoptosis-resistance.