Peng Ying-Yuan, Shi Zhi-Xian, Yu Min, Karam Sami, Chen Zhi-Long, Wang Yang
Department of Pharmacy, Huadong Hospital, Fudan University, Shanghai, China; School of Pharmacy, Fudan University, Shanghai, 201203, China.
School of Pharmacy, Fudan University, Shanghai, 201203, China.
Eur J Med Chem. 2025 Jan 15;282:117090. doi: 10.1016/j.ejmech.2024.117090. Epub 2024 Nov 22.
The emergence of multi-drug resistance (MDR) presents a significant impediment to the efficacy of cancer treatment. Aberrant expression of ABC (ATP-binding cassette) transporters is acknowledged as one of the underlying factors contributing to MDR. P-glycoprotein (P-gp, MDR1, ABCB1), breast cancer resistance protein (BCRP, ABCG2), and MDR-associated protein 1 (MRP1, ABCC1) are members of the ABC transporter, and their over-expression usually occurs in drug-resistant tumor cells. In this work, the structure-activity relationships of the biaryl amide skeleton were systematically investigated via structural optimization step by step, which led to the identification of an exceptionally potent resistance reversal agent, D2. Compound D2 effectively reversed MDR to paclitaxel and cisplatin in A2780/T, A2780/CDDP and A549/T cell lines. It could directly bind to P-gp and downregulate the expression of both P-gp and MRP1. The treatment with D2 increased the intracellular accumulation of Rh123 and inhibited P-gp-mediated drug efflux of Rh123 in A2780/T cells. Therefore, compound D2 exhibits promising potential in overcoming multidrug resistance (MDR) induced by P-gp in cancer.
多药耐药性（MDR）的出现对癌症治疗的疗效构成了重大阻碍。ABC（ATP结合盒）转运蛋白的异常表达被认为是导致MDR的潜在因素之一。P-糖蛋白（P-gp，MDR1，ABCB1）、乳腺癌耐药蛋白（BCRP，ABCG2）和多药耐药相关蛋白1（MRP1，ABCC1）是ABC转运蛋白家族的成员，它们的过表达通常发生在耐药肿瘤细胞中。在这项工作中，通过逐步的结构优化系统地研究了联芳基酰胺骨架的构效关系，从而确定了一种异常有效的耐药逆转剂D2。化合物D2在A2780/T、A2780/CDDP和A549/T细胞系中有效逆转了对紫杉醇和顺铂的MDR。它可以直接与P-gp结合并下调P-gp和MRP1的表达。用D2处理增加了A2780/T细胞中罗丹明123的细胞内积累，并抑制了P-gp介导的罗丹明123的药物外排。因此，化合物D2在克服癌症中由P-gp诱导的多药耐药性（MDR）方面具有广阔的潜力。
