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

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.

Keywords:

• Glutathione S-transferase isozyme mu
• divalent pro-inhibitor
• slow tight-binding inhibitor
• cisplatin-resistance
• sensitisation

Acknowledgements

The athours are particularly grateful to Professor Deqiang Wang at College of Laboratory Medicine at Chongqing Medical University for his help with the crystallization and diffraction data analysis, Professor Jingyuan Wan at the College of Pharmacy at Chongqing Medical University for his help with the cell experiments; Tinghe Yu at Chongqing Medical University and Qing Wu at Shanghai Jiao Tong University for their donation of the test cells.

Disclosure statement

The authors declare that they have no competing interests.

Additional information

Funding

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, CSTC2019jcyj-msxmX0166), Scientific Research Project of the University-Town Hospital of Chongqing Medical University (2021JC03).