Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
J Med Chem. 2011 Jul 28;54(14):4987-97. doi: 10.1021/jm2001663. Epub 2011 Jun 24.
A major challenge in the treatment of cancer is multidrug resistance (MDR) that develops during chemotherapy. Here we demonstrate that tiopronin (1), a thiol-substituted N-propanoylglycine derivative, was selectively toxic to a series of cell lines expressing the drug efflux pump P-glycoprotein (P-gp, ABCB1) and MRP1 (ABCC1). Treatment of MDR cells with 1 led to instability of the ABCB1 mRNA and consequently a reduction in P-gp protein, despite functional assays demonstrating that tiopronin does not interact with P-gp. Long-term exposure of P-gp-expressing cells to 1 sensitized them to doxorubicin and paclitaxel, both P-gp substrates. Treatment of MRP1-overexpressing cells with tiopronin led to a significant reduction in MRP1 protein. Synthesis and screening of analogues of tiopronin demonstrated that the thiol functional group was essential for collateral sensitivity while substitution of the amino acid backbone altered but did not destroy specificity, pointing to future development of targeted analogues.
癌症治疗的一个主要挑战是化疗过程中出现的多药耐药性（MDR）。在这里，我们证明硫普罗宁（1），一种巯基取代的 N-丙酰甘氨酸衍生物，对表达药物外排泵 P 糖蛋白（P-gp，ABCB1）和 MRP1（ABCC1）的一系列细胞系具有选择性毒性。用 1 处理 MDR 细胞会导致 ABCB1 mRNA 不稳定，从而降低 P-gp 蛋白水平，尽管功能测定表明硫普罗宁不与 P-gp 相互作用。长期暴露于 1 会使表达 P-gp 的细胞对多柔比星和紫杉醇（均为 P-gp 底物）敏感。用硫普罗宁处理 MRP1 过表达细胞会导致 MRP1 蛋白显著减少。硫普罗宁类似物的合成和筛选表明，巯基官能团对旁系敏感性至关重要，而氨基酸骨架的取代改变但并未破坏特异性，这指向了靶向类似物的未来发展。
