Revisiting the role of ABC transporters in multidrug-resistant cancer.

Most patients who die of cancer have disseminated disease that has become resistant to multiple therapeutic modalities. Ample evidence suggests that the expression of ATP- binding cassette (ABC) transporters, especially the multidrug resistance protein 1 (MDR1, also known as P- glycoprotein or P-gp), which is encoded by ABC subfamily B member 1 (ABCB1), can confer resistance to cytotoxic and targeted chemotherapy. However, the development of MDR1 as a therapeutic target has been unsuccessful. At the time of its discovery, appropriate tools for the characterization and clinical development of MDR1 as a therapeutic target were lacking. Thirty years after the initial cloning and characterization of MDR1 and the implication of two additional ABC transporters, the multidrug resistance associated protein 1 (MRP1; encoded by ABCC1)), and ABCG2, in multidrug resistance, interest in investigating these transporters as therapeutic targets has waned. However, with the emergence of new data and advanced techniques, we propose to re- evaluate whether these transporters play a clinical role in multidrug resistance. With this Opinion article, we present recent evidence indicating that it is time to revisit the investigation into the role of ABC transporters in efficient drug delivery in various cancer types and at the blood–brain barrier.

大多数死于癌症的患者都患有已对多种治疗方式产生耐药性的播散性疾病。大量证据表明，ATP结合盒（ABC）转运蛋白的表达，尤其是由ABC亚家族B成员1（ABCB1）编码的多药耐药蛋白1（MDR1，也称为P - 糖蛋白或P - gp），可导致对细胞毒性化疗和靶向化疗产生耐药性。然而，将MDR1作为治疗靶点的开发并不成功。在其被发现时，缺乏将MDR1作为治疗靶点进行表征和临床开发的合适工具。在MDR1最初被克隆和表征以及另外两种ABC转运蛋白——多药耐药相关蛋白1（MRP1；由ABCC1编码）和ABCG2被发现与多药耐药有关的30年后，将这些转运蛋白作为治疗靶点进行研究的兴趣已经减弱。然而，随着新数据的出现和先进技术的发展，我们建议重新评估这些转运蛋白在多药耐药中是否具有临床作用。在这篇观点文章中，我们提供了近期的证据，表明是时候重新审视ABC转运蛋白在各种癌症类型以及血脑屏障中有效药物递送方面的作用的研究了。