A Novel Calmodulin Antagonist O-(4-Ethoxyl-Butyl)-Berbamine Overcomes Multidrug Resistance in Drug-Resistant MCF-7/ADR Breast Carcinoma Cells
A Novel Calmodulin Antagonist O-(4-Ethoxyl-Butyl)-Berbamine Overcomes Multidrug Resistance in Drug-Resistant MCF-7/ADR Breast Carcinoma Cells
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新型钙调蛋白拮抗剂 O-(4-乙氧基-丁基)-小檗胺克服耐药 MCF-7/ADR 乳腺癌细胞的多药耐药性
DOI：
10.1002/jps.22082
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发表时间：
2010-07-01
影响因子：
3.8
通讯作者：
Xiong, Dongsheng
中科院分区：
文献类型：
--
作者：
Liu, Rong;Zhang, Yanjun;Xiong, Dongsheng
由药物外排蛋白P-糖蛋白过度表达介导的多药耐药（MDR）是肿瘤化疗成功的主要障碍之一。开发安全有效的MDR逆转剂是临床解决这一问题的重要途径。在这项研究中，我们评估了P-糖蛋白的调节潜力O-（4-乙基丁基）-小檗胺（EBB），一种新的钙调素拮抗剂和衍生物的bisbenzylisoquinoline生物碱，显着提高化疗敏感性的P-糖蛋白介导的多药耐药细胞阿霉素相比，传统的P-糖蛋白抑制剂，维拉帕米的疗效。EBB不仅能阻断P-糖蛋白的功能，还能抑制P-糖蛋白的表达，这一点通过EBB增加罗丹明123和阿霉素在细胞内的蓄积来证实。EBB和阿霉素联合作用可使MCF-7/ADR细胞发生明显的G（2）/M期阻滞和凋亡，并伴有cdc 2/p34和cyclin B1蛋白表达下调和钙离子水平升高。这些结果表明，EBB和阿霉素联合治疗可以显著增强阿霉素的抗肿瘤活性，因此可能在癌症化疗中具有重要的临床应用价值。(C)2010 Wiley-Liss，Inc.和美国药剂师协会药物科学杂志99：3266-3275，2010
Multidrug resistance (MDR) mediated by the overexpression of the drug efflux protein P-glycoprotein is one of the major obstacles to successful cancer chemotherapy. The development of safe and effective MDR-reversing agents is an important approach to addressing this problem clinically. In this study, we evaluated the P-gp-modulatory potential of O-(4-ethoxyl-butyl)-berbamine (EBB), a novel calmodulin antagonist and derivative of bisbenzylisoquinoline alkaloid, which significantly improved the chemosensitivity of P-glycoprotein-mediated multidrug-resistant cells to doxorubicin compared with the efficacy of a conventional P-glycoprotein inhibitor, verapamil. EBB not only blocked the function of P-glycoprotein confirmed by the fact that EBB increased intracellular accumulation of rhodamine 123 and doxorubicin but also inhibited the expression of P-glycoprotein actualized by downregulating P-glycoprotein. Furthermore, our results showed that cotreatment with EBB and doxorubicin resulted in marked G(2)/M arrest and apoptosis of MCF-7/ADR cells, accompanied by down-regulation of the proteins cdc2/p34 and cyclin B1 and increased the levels of calcium ions. Taken together, these results suggest that cotreatment with EBB and doxorubicin could strongly potentiate the antitumor activity of doxorubicin, thus may have significant clinical application in cancer chemotherapy. (C) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3266-3275, 2010