10.6084/M9.FIGSHARE.19195489.V1
Bangtian Xu
Bangtian
Xu
Tingting Tong
Tingting
Tong
Xin Wang
Xin
Wang
Fang Liu
Fang
Liu
Xiang Zhang
Xiang
Zhang
Xiaolei Hu
Xiaolei
Hu
Xinpeng Li
Xinpeng
Li
Xiaolan Yang
Xiaolan
Yang
Fei Liao
Fei
Liao
Short divalent ethacrynic amides as pro-inhibitors of glutathione <i>S</i>-transferase isozyme Mu and potent sensitisers of cisplatin-resistant ovarian cancers
<p>The linking of ethacrynic acid with ethylenediamine and 1,4-butanediamine gave EDEA and BDEA, respectively, as membrane-permeable divalent pro-inhibitors of glutathione <i>S</i>-transferase (GST). Their divalent glutathione conjugates showed subnanomolar inhibition and divalence-binding to GSTmu (GSTM) (PDB: 5HWL) at ∼0.35 min<sup>−1</sup>. 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.</p>
Biophysics
Biochemistry
Microbiology
Cell Biology
Genetics
Molecular Biology
Pharmacology
Biotechnology
Evolutionary Biology
Chemical Sciences not elsewhere classified
Immunology
Biological Sciences not elsewhere classified
Cancer
Hematology
Virology
Taylor & Francis
2022
2022-02-18
2024-03-21
Journal contribution
2465141 Bytes
10.6084/m9.figshare.19195489
10.1080/14756366.2022.2038591
CC BY 4.0