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

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.