Pharmaceutical Institute, Rheinische Friedrich-Wilhelms-University, Bonn, Germany.
Med Res Rev. 2019 Jan;39(1):176-264. doi: 10.1002/med.21510. Epub 2018 May 29.
Multidrug resistance-associated protein 1 (MRP1, ABCC1) is an ATP-binding cassette (ABC) transport protein. This efflux pump uses the energy of ATP hydrolysis to export structurally diverse antineoplastic agents in human cancers. The upregulation of MRP1 (either inherent or acquired) is one major reason for the occurrence of the phenomenon called multidrug resistance (MDR). MDR is characterized by a reduced outcome of chemotherapy due to the active intracellular clearance of cytostatic drugs below the necessary effect concentration. Much effort has been made to overcome MDR, which implied high-throughput screenings of already known pharmacological and natural compounds, modification of intrinsic substrates, as well as design and synthesis of new inhibitors. This review is meant not only to summarize the most recent results over the past 10 years, but also to highlight major achievements regarding reversal of MRP1-mediated MDR, from the time of its discovery until today. The focus lies on small-molecule compounds that feature either direct MRP1 inhibition/transport blockage, toxicity against MRP1-overexpressing cells, inhibition/modification of intracellular processes necessary for MRP1 function, or modification of MRP1-related metabolic and genomic mechanisms. Considering all aspects, this review might be useful to (re)consider possible strategies to overcome MRP1-mediated MDR. Furthermore, it may be the basis for developing new, even better, highly potent, less toxic, and selective (as well as broad-spectrum) MRP1 inhibitors that will enter clinical evaluations in different malignancies and finally conduce to overcome MDR in general.
多药耐药相关蛋白 1（MRP1，ABCC1）是一种 ATP 结合盒（ABC）转运蛋白。这种外排泵利用 ATP 水解的能量将结构多样的抗肿瘤药物从人癌细胞中输出。MRP1 的上调（固有或获得性）是导致多药耐药（MDR）现象发生的主要原因之一。MDR 的特征是由于细胞内细胞毒性药物的清除活性高于必要的效应浓度，导致化疗效果降低。人们已经做出了很大的努力来克服 MDR，这意味着对已经已知的药理学和天然化合物进行高通量筛选、对固有底物进行修饰，以及设计和合成新的抑制剂。这篇综述不仅旨在总结过去 10 年的最新研究结果，还强调了逆转 MRP1 介导的 MDR 的主要成就，从发现到今天。重点是具有直接 MRP1 抑制/转运阻断、针对 MRP1 过表达细胞的毒性、抑制/修饰 MRP1 功能所需的细胞内过程或修饰与 MRP1 相关的代谢和基因组机制的小分子化合物。考虑到所有方面，这篇综述可能有助于（重新）考虑克服 MRP1 介导的 MDR 的可能策略。此外，它可能为开发新的、甚至更好的、高效、低毒和选择性（以及广谱）的 MRP1 抑制剂提供基础，这些抑制剂将在不同的恶性肿瘤中进入临床评估，并最终有助于克服普遍的 MDR。
