ES2 enhances the efficacy of chemotherapeutic agents in ABCB1-overexpressing cancer cells in vitro and in vivo
ES2 enhances the efficacy of chemotherapeutic agents in ABCB1-overexpressing cancer cells in vitro and in vivo
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ES2 在体外和体内增强 ABCB1 过表达癌细胞中化疗药物的疗效
DOI：
10.1016/j.phrs.2017.11.001
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发表时间：
2018-03-01
影响因子：
9.3
通讯作者：
Zhang, Xiongwen
中科院分区：
文献类型：
--
作者：
Fang, Yanfen;Sun, Juanjuan;Zhang, Xiongwen
ES 2是从E. Sororia是中国维吾尔族的传统药物。本文报道了ES 2通过调节ATP结合盒亚家族B成员1（ABCB 1）的功能，在体内外逆转多药耐药（MDR）的作用。ES2对ABCB 1过表达的MDR细胞及其亲本敏感细胞表现出低细胞毒性，但对作为ABCB 1底物的化疗药物敏感MDR细胞和ABCB 1转染的HEK293细胞。ES2的逆转能力主要是由于抑制ABCB 1的外排功能。ES2对ABCB 1的ATP酶活性具有浓度依赖性。在ES2的存在下，ABCB 1的表达没有变化。分子对接分析表明ES2与ABCBI转运蛋白的药物结合位点结合。重要的是，ES2显著增强长春瑞滨对裸鼠KBv200细胞异种移植物的抗肿瘤作用。总之，这些发现表明，ES2抑制ABCB 1转运蛋白功能，从而逆转ABCB 1介导的MDR，表明ES2与传统化疗药物联合治疗癌症的潜在用途。(C)2017爱思唯尔有限公司版权所有
ES2 is a new type of jatrophane diterpenoid ester isolated from the fructus E. sororia, a traditional Uyghur medicine in China. Here we reported the multidrug resistance (MDR) reversal effect of ES2 in vitro and in vivo by modulating the function of ATP-binding cassette subfamily B member 1 (ABCB1). ES2 exhibited low cytotoxicity to ABCB1-overexpressing MDR cells and their parental sensitive cells, but sensitized the MDR cells and ABCB1-transfected HEK293 cells to chemotherapeutic drugs that are ABCB1 substrates. The reversal ability of ES2 was primarily due to the inhibition of the efflux function of ABCB1. Moreover, ES2 stimulated the ATPase activity of ABCB1 in a concentration-dependent manner. There was no change in the expression of ABCB1 in the presence of ES2. The molecular docking analysis indicated that ES2 bond to the drug-binding site of ABCBI transporter. Importantly, ES2 significantly enhanced the anti-tumor effect of vinorelbine against KBv200 cell xenografts in nude mice. Overall, these findings demonstrate that ES2 inhibits the ABCB1 transporter function and consequently reverses ABCB1-mediated MDR, indicating the potential use of ES2 in combination therapy with conventional chemotherapeutic drugs for cancer treatment. (C) 2017 Elsevier Ltd. All rights reserved.