Reversal effects of two new milbemycin compounds on multidrug resistance in MCF-7/adr cells in vitro
Reversal effects of two new milbemycin compounds on multidrug resistance in MCF-7/adr cells in vitro
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两种新的米尔贝霉素化合物对 MCF-7/adr 细胞多药耐药的体外逆转作用
DOI：
10.1016/j.ejphar.2011.03.023
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发表时间：
2011-06-01
影响因子：
5
通讯作者：
Xiang, Wensheng
中科院分区：
文献类型：
--
作者：
Gao, Aili;Liang, Hongsheng;Xiang, Wensheng
肿瘤多药耐药（multidrug resistance，MDR）是肿瘤化疗中的一个重要问题，而P-糖蛋白（P-gp）的过度表达是肿瘤多药耐药的主要机制之一。本文研究了两个新的米尔贝霉素化合物米尔贝霉素β（14）和Secomilbemycin D，它们是从S.冰城根对人乳腺癌耐阿霉素细胞（MCF-7/adr）多药耐药的逆转作用。我们观察到，两种米尔贝霉素（5 μ M）显示出很强的效力，增加阿霉素对MCF-7/adr细胞的细胞毒性，逆转倍数（RF）分别为13.5和10.59。此外，米尔倍霉素逆转P-gp介导的MDR的机制表明，米尔倍霉素通过抑制P-gp外排，增加阿霉素和Rh 123在MCF-7/adr细胞中的蓄积。米尔贝霉素β（14）和裂孔米尔贝霉素D可下调P-gp的表达，但不影响MDR 1基因的表达。总之，我们的观察表明，这两个新的米尔贝霉素化合物可能代表有前途的药物逆转多药耐药的癌症治疗。(C)2011 Elsevier B. V.保留所有权利。
Development of agents to overcome multidrug resistance (MDR) is important in cancer chemotherapy, and the overexpression of P-glycoprotein (P-gp) is one of the major mechanisms of MDR. In this paper, we evaluated the effects of two new milbemycin compounds, milbemycin beta(14) and secomilbemycin D, isolated from fermentation broth of S. bingchenggensis on reversing MDR of adriamycin-resistant human breast carcinoma (MCF-7/adr) cells. We observed that the both milbemycins (5 mu M) showed strong potency to increase adriamycin cytotoxicity toward MCF-7/adr cells with reversal fold (RF) of 13.5 and 10.59, respectively. In addition, the mechanisms of milbemycins on reversing P-gp-mediated MDR demonstrated that they significantly increased the accumulations of adriamycin and Rh123 via inhibiting P-gp efflux in MCF-7/adr cells. Furthermore, the results also revealed that milbemycin beta(14) and secomilbemycin D could regulate down the expression of P-gp, but not affect the expression of MDR1 gene. In conclusion, our observations suggest that the two new milbemycin compounds probably represent the promising agents for reversing MDR in cancer therapy. (C) 2011 Elsevier B.V. All rights reserved.