克服 ABCB1 和 ABCG2 介导的癌症多药耐药性的药物再利用策略。

Perspectives on drug repurposing to overcome cancer multidrug resistance mediated by ABCB1 and ABCG2.

机构信息

Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan.

Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.

出版信息

Drug Resist Updat. 2023 Nov;71:101011. doi: 10.1016/j.drup.2023.101011. Epub 2023 Oct 10.

DOI:10.1016/j.drup.2023.101011

PMID:37865067

Abstract

The overexpression of the human ATP-binding cassette (ABC) transporters in cancer cells is a common mechanism involved in developing multidrug resistance (MDR). Unfortunately, there are currently no approved drugs specifically designed to treat multidrug-resistant cancers, making MDR a significant obstacle to successful chemotherapy. Despite over two decades of research, developing transporter-specific inhibitors for clinical use has proven to be a challenging endeavor. As an alternative approach, drug repurposing has gained traction as a more practical method to discover clinically effective modulators of drug transporters. This involves exploring new indications for already-approved drugs, bypassing the lengthy process of developing novel synthetic inhibitors. In this context, we will discuss the mechanisms of ABC drug transporters ABCB1 and ABCG2, their roles in cancer MDR, and the inhibitors that have been evaluated for their potential to reverse MDR mediated by these drug transporters. Our focus will be on providing an up-to-date report on approved drugs tested for their inhibitory activities against these drug efflux pumps. Lastly, we will explore the challenges and prospects of repurposing already approved medications for clinical use to overcome chemoresistance in patients with high tumor expression of ABCB1 and/or ABCG2.

摘要

人 ATP 结合盒（ABC）转运蛋白在癌细胞中的过度表达是一种常见的多药耐药（MDR）相关机制。不幸的是，目前尚无专门用于治疗多药耐药癌症的批准药物，这使得 MDR 成为化疗成功的重大障碍。尽管经过了二十多年的研究，开发针对转运蛋白的特异性抑制剂用于临床已被证明是一项具有挑战性的工作。作为一种替代方法，药物再利用作为一种更实用的方法来发现药物转运蛋白的临床有效调节剂已引起关注。这涉及探索已批准药物的新适应症，从而绕过开发新型合成抑制剂的漫长过程。在这种情况下，我们将讨论 ABC 药物转运蛋白 ABCB1 和 ABCG2 的机制、它们在癌症 MDR 中的作用，以及已评估的抑制剂，以评估它们逆转这些药物转运蛋白介导的 MDR 的潜力。我们的重点将是提供一份关于已批准药物的最新报告，这些药物已针对其对这些药物外排泵的抑制活性进行了测试。最后，我们将探讨重新利用已批准药物用于临床以克服 ABCB1 和/或 ABCG2 高肿瘤表达患者的化疗耐药性的挑战和前景。