VS-4718 Antagonizes Multidrug Resistance in ABCB1- and ABCG2-Overexpressing Cancer Cells by Inhibiting the Efflux Function of ABC Transporters.
VS-4718 Antagonizes Multidrug Resistance in ABCB1- and ABCG2-Overexpressing Cancer Cells by Inhibiting the Efflux Function of ABC Transporters.
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VS-4718 通过抑制 ABC 转运蛋白的外排功能来拮抗 ABCB1 和 ABCG2 过表达癌细胞的多药耐药性。
DOI：
10.3389/fphar.2018.01236
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发表时间：
2018
影响因子：
5.6
通讯作者：
Yang DH
中科院分区：
文献类型：
--
作者：
Ji N;Yang Y;Cai CY;Lei ZN;Wang JQ;Gupta P;Teng QX;Chen ZS;Kong D;Yang DH
ATP结合盒（ABC）转运蛋白的过度表达是导致多药耐药（MDR）的重要机制之一。VS-4718是一种以粘着斑激酶（FAK）为靶点的酪氨酸激酶抑制剂，具有潜在的抗癌作用，目前正在临床试验中进行评估。在这项研究中，我们研究了VS-4718是否可以逆转ABC转运蛋白介导的MDR，包括ABCB 1，ABCG 2和ABCC 1。结果表明，VS-4718可显著逆转ABCB 1和ABCG 2介导的MDR，但对ABCC 1介导的MDR无明显影响。VS-4718处理未改变ABCB 1或ABCG 2的蛋白水平和亚细胞定位。机制研究表明，VS-4718的逆转作用与ABCB 1和ABCG 2转运体的外排活性减弱有关。ATP酶分析表明VS-4718对ABCB 1和ABCG 2的ATP酶活性有促进作用。对接研究表明VS-4718与ABCB 1和ABCG 2的底物结合位点都有相互作用，表明VS-4718可能竞争性影响ABCB 1和ABCG 2的活性。本研究为MDR肿瘤的治疗提供了新的思路。表明VS-4718联合化疗药物可减弱ABCB 1或ABCG 2过表达癌细胞中ABCB 1或ABCG 2介导的MDR。
Overexpression of ATP-binding cassette (ABC) transporters is one of the most important mechanisms responsible for multi-drug resistance (MDR). VS-4718, a tyrosine kinase inhibitor targeting focal adhesion kinase (FAK) with a potential anticancer effect, is currently evaluated in clinical trials. In this study, we investigated whether VS-4718 could reverse MDR mediated by ABC transporters, including ABCB1, ABCG2, and ABCC1. The results showed that VS-4718 significantly reversed ABCB1- and ABCG2-mediated MDR, but not MDR mediated by ABCC1. Treatment of VS-4718 did not alter the protein level and subcellular localization of ABCB1 or ABCG2. Mechanism studies indicated that the reversal effects of VS-4718 were related to attenuation of the efflux activity of ABCB1 and ABCG2 transporters. ATPase analysis indicated that VS-4718 stimulated the ATPase activity of ABCB1 and ABCG2. Docking study showed that VS-4718 interacted with the substrate-binding sites of both ABCB1 and ABCG2, suggesting that VS-4718 may affect the activity of ABCB1 and ABCG2 competitively. This study provided a novel insight for MDR cancer treatment. It indicated that combination of VS-4718 with antineoplastic drugs could attenuate MDR mediated by ABCB1 or ABCG2 in ABCB1- or ABCG2-overexpressing cancer cells.
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影响因子：
11.2
作者：
Fung KL;Pan J;Ohnuma S;Lund PE;Pixley JN;Kimchi-Sarfaty C;Ambudkar SV;Gottesman MM
通讯作者：
Gottesman MM
影响因子：
8
作者：
Li, Jingzhi;Jaimes, Kimberly F.;Aller, Stephen G.
通讯作者：
Aller, Stephen G.
影响因子：
11.2
作者：
Dai CL;Tiwari AK;Wu CP;Su XD;Wang SR;Liu DG;Ashby CR Jr;Huang Y;Robey RW;Liang YJ;Chen LM;Shi CJ;Ambudkar SV;Chen ZS;Fu LW
通讯作者：
Fu LW
影响因子：
64.5
作者：
Serrels A;Lund T;Serrels B;Byron A;McPherson RC;von Kriegsheim A;Gómez-Cuadrado L;Canel M;Muir M;Ring JE;Maniati E;Sims AH;Pachter JA;Brunton VG;Gilbert N;Anderton SM;Nibbs RJ;Frame MC
通讯作者：
Frame MC
影响因子：
2.9
作者：
BATES, SE;LEE, JS;FOJO, AT
通讯作者：
FOJO, AT