FRAX486, a PAK inhibitor, overcomes ABCB1-mediated multidrug resistance in breast cancer cells.

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Accounts of Chemical Research Pub Date : 2024-07-01 eCollection Date: 2024-01-01 DOI:10.1590/1414-431X2024e13357

Meng Zhang, Xiaoqi Zeng, Meiling She, Xingduo Dong, Jun Chen, Qingquan Xiong, Guobin Qiu, Shuyi Yang, Xiangqi Li, Guanghui Ren

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Abstract

The overexpression of P-glycoprotein (P-gp/ABCB1) is a leading cause of multidrug resistance (MDR). Hence, it is crucial to discover effective pharmaceuticals that counteract ABCB1-mediated multidrug resistance. FRAX486 is a p21-activated kinase (PAK) inhibitor. The objective of this study was to investigate whether FRAX486 can reverse ABCB1-mediated multidrug resistance, while also exploring its mechanism of action. The CCK8 assay demonstrated that FRAX486 significantly reversed ABCB1-mediated multidrug resistance. Furthermore, western blotting and immunofluorescence experiments revealed that FRAX486 had no impact on expression level and intracellular localization of ABCB1. Notably, FRAX486 was found to enhance intracellular drug accumulation and reduce efflux, resulting in the reversal of multidrug resistance. Docking analysis also indicated a strong affinity between FRAX486 and ABCB1. This study highlights the ability of FRAX486 to reverse ABCB1-mediated multidrug resistance and provides valuable insights for its clinical application.

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PAK抑制剂FRAX486能克服乳腺癌细胞中ABCB1介导的多药耐药性。

P-糖蛋白（P-gp/ABCB1）的过度表达是导致多药耐药性（MDR）的主要原因。因此，发现能对抗 ABCB1 介导的多药耐药性的有效药物至关重要。FRAX486 是一种 p21 激活激酶（PAK）抑制剂。本研究旨在探讨 FRAX486 能否逆转 ABCB1 介导的多药耐药性，同时探索其作用机制。CCK8试验表明，FRAX486能显著逆转ABCB1介导的多药耐药性。此外，Western 印迹和免疫荧光实验显示，FRAX486 对 ABCB1 的表达水平和细胞内定位没有影响。值得注意的是，FRAX486 能增强药物在细胞内的蓄积并减少外流，从而逆转多药耐药性。对接分析还表明 FRAX486 与 ABCB1 有很强的亲和力。这项研究强调了 FRAX486 逆转 ABCB1 介导的多药耐药性的能力，并为其临床应用提供了宝贵的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.