Resistance to chemotherapy remains one of the most significant obstacles to successful cancer treatment. While inhibiting drug efflux mediated by ATP-binding cassette (ABC) transporters is a seemingly attractive and logical approach to combat multidrug resistance (MDR), small molecule inhibition of ABC transporters has so far failed to confer clinical benefit, despite considerable efforts by medicinal chemists, biologists, and clinicians. The long-sought treatment to eradicate cancers displaying ABC transporter overexpression may therefore lie within alternative targeting strategies. When aberrantly expressed, the ABC transporter multidrug resistance-associated protein 1 (MRP1, ABCC1) confers MDR, but can also shift cellular redox balance, leaving the cell vulnerable to select agents. Here, we explore the physiological roles of MRP1, the rational for targeting this transporter in cancer, the development of small molecule MRP1 inhibitors, and the most recent developments in alternative therapeutic approaches for targeting cancers with MRP1 overexpression. We discuss approaches that extend beyond simple MRP1 inhibition by exploiting the collateral sensitivity to glutathione depletion and ferroptosis, the rationale for targeting the shared transcriptional regulators of both MRP1 and glutathione biosynthesis, advances in gene silencing, and new molecules that modulate transporter activity to the detriment of the cancer cell. These strategies illustrate promising new approaches to address multidrug resistant disease that extend beyond the simple reversal of MDR and offer exciting routes for further research.

对化疗的耐药性仍然是成功治疗癌症的最重要障碍之一。虽然抑制由 ATP 结合盒 (ABC) 转运蛋白介导的药物流出是对抗多药耐药 (MDR) 的一种看似有吸引力且合乎逻辑的方法，但迄今为止，尽管药物化学家付出了相当大的努力，但对 ABC 转运蛋白的小分子抑制未能带来临床益处、生物学家和临床医生。因此，长期寻求的根除显示 ABC 转运蛋白过度表达的癌症的治疗可能属于替代靶向策略。当异常表达时，ABC 转运蛋白多药耐药相关蛋白 1（MRP1、ABCC1) 赋予 MDR，但也可以改变细胞的氧化还原平衡，使细胞容易受到选择试剂的影响。在这里，我们探讨了 MRP1 的生理作用，在癌症中靶向这种转运蛋白的合理性，小分子 MRP1 抑制剂的开发，以及靶向 MRP1 过表达癌症的替代治疗方法的最新进展。我们通过利用对谷胱甘肽消耗和铁死亡的附带敏感性，讨论了超越简单 MRP1 抑制的方法，靶向 MRP1 和谷胱甘肽生物合成的共享转录调节因子的基本原理，基因沉默的进展，以及调节转运蛋白活性的新分子有害的癌细胞。