Goebel Jason, Chmielewski Jean, Hrycyna Christine A
Department of Chemistry, Purdue University West Lafayette, IN 47907, USA.
Cancer Drug Resist. 2021;4(4):784-804. doi: 10.20517/cdr.2021.19. Epub 2021 Aug 4.
The ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp) and ABCG2 are multidrug transporters that confer drug resistance to numerous anti-cancer therapeutics in cell culture. These findings initially created great excitement in the medical oncology community, as inhibitors of these transporters held the promise of overcoming clinical multidrug resistance in cancer patients. However, clinical trials of P-gp and ABCG2 inhibitors in combination with cancer chemotherapeutics have not been successful due, in part, to flawed clinical trial designs resulting from an incomplete molecular understanding of the multifactorial basis of multidrug resistance (MDR) in the cancers examined. The field was also stymied by the lack of high-resolution structural information for P-gp and ABCG2 for use in the rational structure-based drug design of inhibitors. Recent advances in structural biology have led to numerous structures of both ABCG2 and P-gp that elucidated more clearly the mechanism of transport and the polyspecific nature of their substrate and inhibitor binding sites. These data should prove useful helpful for developing even more potent and specific inhibitors of both transporters. As such, although possible pharmacokinetic interactions would need to be evaluated, these inhibitors may show greater effectiveness in overcoming ABC-dependent multidrug resistance in combination with chemotherapeutics in carefully selected subsets of cancers. Another perhaps even more compelling use of these inhibitors may be in reversibly inhibiting endogenously expressed P-gp and ABCG2, which serve a protective role at various blood-tissue barriers. Inhibition of these transporters at sanctuary sites such as the brain and gut could lead to increased penetration by chemotherapeutics used to treat brain cancers or other brain disorders and increased oral bioavailability of these agents, respectively.
ATP结合盒（ABC）转运蛋白P-糖蛋白（P-gp）和ABCG2是多药转运蛋白，在细胞培养中可赋予多种抗癌治疗药物耐药性。这些发现最初在医学肿瘤学界引起了极大的轰动，因为这些转运蛋白的抑制剂有望克服癌症患者的临床多药耐药性。然而，P-gp和ABCG2抑制剂与癌症化疗药物联合使用的临床试验并未成功，部分原因是临床试验设计存在缺陷，这是由于对所研究癌症中多药耐药（MDR）的多因素基础缺乏完整的分子理解所致。该领域还因缺乏用于基于合理结构的抑制剂药物设计的P-gp和ABCG2的高分辨率结构信息而受阻。结构生物学的最新进展已产生了ABCG2和P-gp的多种结构，这些结构更清楚地阐明了转运机制及其底物和抑制剂结合位点的多特异性性质。这些数据对于开发更有效和更特异的两种转运蛋白抑制剂应该是有用的。因此，尽管需要评估可能的药代动力学相互作用，但这些抑制剂在精心挑选的癌症亚组中与化疗药物联合使用时，可能在克服ABC依赖性多药耐药方面显示出更大的有效性。这些抑制剂的另一个可能更具吸引力的用途可能是可逆地抑制内源性表达的P-gp和ABCG2，它们在各种血组织屏障中起保护作用。在脑和肠道等庇护部位抑制这些转运蛋白可能分别导致用于治疗脑癌或其他脑部疾病的化疗药物的渗透性增加以及这些药物的口服生物利用度增加。
