Short divalent ethacrynic amides as pro-inhibitors of glutathione S-transferase isozyme Mu and potent sensitisers of cisplatin-resistant ovarian cancers

作者全名："Xu, Bangtian; Tong, Tingting; Wang, Xin; Liu, Fang; Zhang, Xiang; Hu, Xiaolei; Li, Xinpeng; Yang, Xiaolan; Liao, Fei"

作者地址："[Xu, Bangtian; Tong, Tingting; Wang, Xin; Liu, Fang; Zhang, Xiang; Hu, Xiaolei; Li, Xinpeng; Yang, Xiaolan; Liao, Fei] Chongqing Med Univ, Coll Lab Med, Key Lab Clin Lab Diagnost, Educ Minist, Chongqing 400016, Peoples R China; [Xu, Bangtian] Chongqing Med Univ, Dept Pharm, Univ Town Hosp, Chongqing, Peoples R China"

通信作者："Yang, XL; Liao, F (通讯作者)，Chongqing Med Univ, Coll Lab Med, Key Lab Clin Lab Diagnost, Educ Minist, Chongqing 400016, Peoples R China."

来源：JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000757635100001

JCR分区：Q1

影响因子：5.6

年份：2022

卷号：37

期号：1

开始页：728

结束页：742

文献类型：Article

关键词：Glutathione S-transferase isozyme mu; divalent pro-inhibitor; slow tight-binding inhibitor; cisplatin-resistance; sensitisation

摘要："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 similar to 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 mu M sensitised resistant SK-OV-3 and COC1 cells by similar to 3- and similar to 5-folds, respectively, released cytochrome c and increased apoptosis; EDEA at 1.0 mu M sensitised resistant SK-OV-3 and A549 cells by similar to 5- and similar to 7-fold, respectively. EDEA at 1.7 mu g/g sensitised resistant SK-OV-3 cells to cisplatin at 3.3 mu g/g in nude mouse xenograft model. BDEA and EDEA are promising leads for probing cellular GSTM and sensitising cisplatin-resistant ovarian cancers."

基金机构："National Natural Science Foundation of China [81773625, 81071427, 31570862]; Ph.D. Programs Foundation of Ministry of Education of the People's Republic of China [20125503110007]; Natural Science Foundation Project of Chongqing; Chongqing Science and Technology Commission [CSTC2012JJA0057, CSTC2019jcyjmsxmX0166]; Scientific Research Project of the University-Town Hospital of Chongqing Medical University [2021JC03]"

基金资助正文："This work was supported by National Natural Science Foundation of China (grant nos. 81773625, 81071427, 31570862), Ph.D. Programs Foundation of Ministry of Education of the People's Republic of China (no.20125503110007), Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission (CSTC2012JJA0057, CSTC2019jcyjmsxmX0166), Scientific Research Project of the University-Town Hospital of Chongqing Medical University (2021JC03)."