Pharmaceutical Sciences Graduation Program, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, PR, Brazil.
Pharmaceutical Sciences Graduation Program, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, PR, Brazil.
Eur J Med Chem. 2022 Jul 5;237:114346. doi: 10.1016/j.ejmech.2022.114346. Epub 2022 Apr 6.
The primary source of failure of cancer therapies is multidrug resistance (MDR), which can be caused by different mechanisms, including the overexpression of ABC transporters in cancer cells. Among the 48 human ABC proteins, the breast cancer resistance protein (BCRP/ABCG2) has been described as a pivotal player in cancer resistance. The use of functional inhibitors and expression modulators is a promising strategy to overcome the MDR caused by ABCG2. Despite the lack of clinical trials using ABCG2 inhibitors, many compounds have already been discovered. This review presents an overview about various ABCG2 inhibitors that have been identified, discussing some chemical aspects and the main experimental methods used to identify and characterize the mechanisms of new inhibitors. In addition, some biological requirements to pursue preclinical tests are described. Finally, we discuss the potential use of ABCG2 inhibitors in cancer stem cells (CSC) for improving the objective response rate and the mechanism of ABCG2 modulators at transcriptional and protein expression levels.
癌症治疗失败的主要原因是多药耐药性（MDR），其可由多种机制引起，包括 ABC 转运蛋白在癌细胞中的过度表达。在 48 个人类 ABC 蛋白中，乳腺癌耐药蛋白（BCRP/ABCG2）已被描述为癌症耐药性的关键因素。使用功能抑制剂和表达调节剂是克服 ABCG2 引起的 MDR 的有前途的策略。尽管缺乏使用 ABCG2 抑制剂的临床试验，但已经发现了许多化合物。本综述介绍了已鉴定的各种 ABCG2 抑制剂，讨论了一些化学方面以及用于鉴定和表征新抑制剂机制的主要实验方法。此外，还描述了进行临床前试验的一些生物学要求。最后，我们讨论了 ABCG2 抑制剂在癌症干细胞（CSC）中的潜在用途，以提高客观缓解率和 ABCG2 调节剂在转录和蛋白表达水平上的作用机制。
