Pan Chao, Lee Leo Tsz On
Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau, China; Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau, China.
Biochim Biophys Acta Rev Cancer. 2025 Apr;1880(2):189272. doi: 10.1016/j.bbcan.2025.189272. Epub 2025 Jan 23.
Chemoresistance is a multifactorial phenomenon and the primary cause to the ineffectiveness of oncotherapy and cancer recurrence. Membrane drug transporters are crucial for drug delivery and disposition in cancer cells. Changes in the expression and functionality of these transporters lead to decreased intracellular accumulation and reduced toxicity of antineoplastic drugs. As the mechanism has been better understood and genetic engineering technology progressed quickly in recent years, some novel targeting strategies have come to light. This article summarizes the regulatory mechanisms of membrane drug transporters and provides an extensive review of current approaches to address transporters-mediated chemoresistance. These strategies include the use of chemical inhibitors to block efflux transporters, the development of copper chelators to enhance platinum drug uptake, the delivery of genetic drugs to alter transporter expression, the regulation of transcription and post-translational modifications. Additionally, we provide information of the clinical trial performance of the related targeting strategies, along with the ongoing challenges. Even though some clinical trials failed due to unexpected side effects and limited therapeutic efficacy, the advent of targeting membrane drug transporters still presents a hopeful path for overcoming chemoresistance.
化疗耐药是一种多因素现象，也是肿瘤治疗无效和癌症复发的主要原因。膜药物转运蛋白对于癌细胞中的药物递送和处置至关重要。这些转运蛋白表达和功能的变化会导致细胞内药物积累减少以及抗肿瘤药物毒性降低。随着近年来该机制得到更好的理解且基因工程技术迅速发展，一些新型靶向策略应运而生。本文总结了膜药物转运蛋白的调控机制，并对目前解决转运蛋白介导的化疗耐药的方法进行了广泛综述。这些策略包括使用化学抑制剂阻断外排转运蛋白、开发铜螯合剂以增强铂类药物摄取、递送基因药物以改变转运蛋白表达、调控转录和翻译后修饰。此外，我们还提供了相关靶向策略的临床试验表现信息以及面临的持续挑战。尽管一些临床试验因意外的副作用和有限的治疗效果而失败，但靶向膜药物转运蛋白的出现仍然为克服化疗耐药提供了一条充满希望的途径。
