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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过表达癌细胞中的多药耐药性。

VS-4718 Antagonizes Multidrug Resistance in ABCB1- and ABCG2-Overexpressing Cancer Cells by Inhibiting the Efflux Function of ABC Transporters.

作者信息

Ji Ning, Yang Yuqi, Cai Chao-Yun, Lei Zi-Ning, Wang Jing-Quan, Gupta Pranav, Teng Qiu-Xu, Chen Zhe-Sheng, Kong Dexin, Yang Dong-Hua

机构信息

Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

出版信息

Front Pharmacol. 2018 Oct 30;9:1236. doi: 10.3389/fphar.2018.01236. eCollection 2018.

DOI:10.3389/fphar.2018.01236
PMID:30425643
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6218957/
Abstract

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.

摘要

ATP结合盒（ABC）转运蛋白的过表达是导致多药耐药（MDR）的最重要机制之一。VS-4718是一种靶向粘着斑激酶（FAK）的酪氨酸激酶抑制剂，具有潜在的抗癌作用，目前正在进行临床试验评估。在本研究中，我们调查了VS-4718是否能逆转由ABC转运蛋白介导的多药耐药，包括ABCB1、ABCG2和ABCC1。结果表明，VS-4718能显著逆转ABCB1和ABCG2介导的多药耐药，但不能逆转ABCC1介导的多药耐药。VS-4718处理并未改变ABCB1或ABCG2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ABCB1和ABCG2转运蛋白外排活性的减弱有关。ATP酶分析表明，VS-4718刺激了ABCB1和ABCG2的ATP酶活性。对接研究表明，VS-4718与ABCB1和ABCG2的底物结合位点相互作用，提示VS-4718可能竞争性地影响ABCB1和ABCG2的活性。本研究为多药耐药癌症的治疗提供了新的见解。结果表明，VS-4718与抗肿瘤药物联合应用可减弱ABCB1或ABCG2过表达癌细胞中由ABCB1或ABCG2介导的多药耐药。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c262/6218957/f188d99e763d/fphar-09-01236-g0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c262/6218957/3667ac0da2c6/fphar-09-01236-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c262/6218957/d60b144a5253/fphar-09-01236-g0002.jpg
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