Abstract

The linking of ethacrynic acid with ethylenediamine and 1,4-butanediamine gave EDEA and BDEA, respectively, as membrane-permeable divalent pro-inhibitors of glutathione S-transferase (GST). Their divalent glutathione conjugates showed subnanomolar inhibition and divalence-binding to GSTmu (GSTM) (PDB: 5HWL) at ∼0.35 min⁻¹. In cisplatin-resistant SK-OV-3, COC1, SGC7901 and A549 cells, GSTM activities probed by 15 nM BDEA or EDEA revealed 5-fold and 1.0-fold increases in cisplatin-resistant SK-OV-3 and COC1 cells, respectively, in comparison with the susceptible parental cells. Being tolerable by HEK293 and LO2 cells, BDEA at 0.2 μM sensitised resistant SK-OV-3 and COC1 cells by ∼3- and ∼5-folds, respectively, released cytochrome c and increased apoptosis; EDEA at 1.0 μM sensitised resistant SK-OV-3 and A549 cells by ∼5- and ∼7-fold, respectively. EDEA at 1.7 μg/g sensitised resistant SK-OV-3 cells to cisplatin at 3.3 μg/g in nude mouse xenograft model. BDEA and EDEA are promising leads for probing cellular GSTM and sensitising cisplatin-resistant ovarian cancers.

摘要

乙基丙烯酸与乙二胺和 1,4-丁二胺的连接分别产生 EDEA 和 BDEA，作为谷胱甘肽S-转移酶 (GST) 的膜可渗透二价前抑制剂。^{他们的二价谷胱甘肽缀合物在~0.35 min -1}时显示出亚纳摩尔抑制和与 GSTmu (GSTM) (PDB: 5HWL) 的二价结合. 在顺铂耐药的 SK-OV-3、COC1、SGC7901 和 A549 细胞中，15 nM BDEA 或 EDEA 探测的 GSTM 活性显示，顺铂耐药的 SK-OV-3 和 COC1 细胞分别增加了 5 倍和 1.0 倍，与易感亲代细胞相比。HEK293 和 LO2 细胞可以耐受，0.2 μM 的 BDEA 分别使抗性 SK-OV-3 和 COC1 细胞致敏约 3 倍和 5 倍，释放细胞色素 c 并增加细胞凋亡；1.0 μM 的 EDEA 分别使抗性 SK-OV-3 和 A549 细胞致敏 5 倍和 7 倍。在裸鼠异种移植模型中，1.7 μg/g 的 EDEA 致敏抗性 SK-OV-3 细胞对 3.3 μg/g 的顺铂。BDEA 和 EDEA 是探索细胞 GSTM 和敏感顺铂耐药卵巢癌的有希望的线索。