Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, 310022, China; College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
Research Center of Biochemical Engineering Technology, College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou 425199, China.
Drug Resist Updat. 2020 Mar;49:100681. doi: 10.1016/j.drup.2020.100681. Epub 2020 Jan 22.
The presence of multidrug resistance (MDR) in malignant tumors is one of the primary causes of treatment failure in cancer chemotherapy. The overexpression of the ATP binding cassette (ABC) transporter, P-glycoprotein (P-gp), which significantly increases the efflux of certain anticancer drugs from tumor cells, produces MDR. Therefore, inhibition of P-gp may represent a viable therapeutic strategy to overcome cancer MDR. Over the past 4 decades, many compounds with P-gp inhibitory efficacy (referred to as first- and second-generation P-gp inhibitors) have been identified or synthesized. However, these compounds were not successful in clinical trials due to a lack of efficacy and/or untoward toxicity. Subsequently, third- and fourth-generation P-gp inhibitors were developed but dedicated clinical trials did not indicate a significant therapeutic effect. In recent years, an extraordinary array of highly potent, selective, and low-toxicity P-gp inhibitors have been reported. Herein, we provide a comprehensive review of the synthetic and natural products that have specific inhibitory activity on P-gp drug efflux as well as promising chemosensitizing efficacy in MDR cancer cells. The present review focuses primarily on the structural features, design strategies, and structure-activity relationships (SAR) of these compounds.
多药耐药（MDR）在恶性肿瘤中的存在是癌症化疗治疗失败的主要原因之一。ATP 结合盒（ABC）转运蛋白 P-糖蛋白（P-gp）的过度表达，显著增加了某些抗癌药物从肿瘤细胞中的外排，导致 MDR。因此，抑制 P-gp 可能代表一种可行的治疗策略，以克服癌症的 MDR。在过去的 40 年中，已经鉴定或合成了许多具有 P-gp 抑制作用的化合物（称为第一代和第二代 P-gp 抑制剂）。然而，由于疗效不足和/或不良反应毒性，这些化合物在临床试验中并未成功。随后，开发了第三代和第四代 P-gp 抑制剂，但专门的临床试验并未表明有显著的治疗效果。近年来，报道了大量高效、选择性和低毒性的 P-gp 抑制剂。本文全面综述了对 P-gp 药物外排具有特异性抑制活性以及在 MDR 癌细胞中具有有前途的化疗增敏作用的合成和天然产物。本综述主要关注这些化合物的结构特征、设计策略和构效关系（SAR）。
