Tia Shi Ting, Luo Min, Fan Wenjie
Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore.
Center for Bioimaging Sciences, Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
Int J Mol Sci. 2025 Apr 28;26(9):4179. doi: 10.3390/ijms26094179.
P-glycoprotein (P-gp/ABCB1), a key ATP-binding cassette (ABC) transporter, plays a central role in multidrug resistance (MDR), one of the leading causes of chemotherapy failure in cancer treatment. P-gp actively pumps chemotherapeutic agents out of cancer cells, reducing intracellular drug concentration and compromising therapeutic efficacy. Recent advancements in structural biology, particularly cryogenic electron microscopy (cryo-EM), have revealed detailed conformational states of P-gp, providing unprecedented insights into its transport mechanisms. In parallel, studies have identified various P-gp mutants in cancer patients, many of which are linked to altered drug efflux activity and resistance phenotypes. This review systematically examines recent structural studies of P-gp, correlates known patient-derived mutations to their functional consequences, and explores their impact on MDR. We propose plausible mechanisms by which these mutations affect P-gp's activity based on structural evidence and discuss their implications for chemotherapy resistance. Additionally, we review current approaches for P-gp inhibition, a critical strategy to restore drug sensitivity in resistant cancers, and outline future research directions to combat P-gp-mediated MDR.
P-糖蛋白（P-gp/ABCB1）是一种关键的ATP结合盒（ABC）转运蛋白，在多药耐药性（MDR）中起核心作用，MDR是癌症治疗中化疗失败的主要原因之一。P-糖蛋白能主动将化疗药物泵出癌细胞，降低细胞内药物浓度并削弱治疗效果。结构生物学的最新进展，特别是低温电子显微镜（cryo-EM）技术，揭示了P-糖蛋白的详细构象状态，为其转运机制提供了前所未有的见解。与此同时，研究在癌症患者中发现了各种P-糖蛋白突变体，其中许多与药物外排活性改变和耐药表型有关。本综述系统地研究了P-糖蛋白的近期结构研究，将已知的患者来源突变与其功能后果相关联，并探讨它们对多药耐药性的影响。我们基于结构证据提出了这些突变影响P-糖蛋白活性的合理机制，并讨论了它们对化疗耐药性的影响。此外，我们综述了目前抑制P-糖蛋白的方法，这是恢复耐药癌症药物敏感性的关键策略，并概述了对抗P-糖蛋白介导的多药耐药性的未来研究方向。
