Combination therapy with Selenourea and Ethacrynic acid targeting GST inhibition and reveals some apoptosis-cleaved proteins in breast cancer

Abstract Abstract Objective: Glutathione S-transferase (GST) participates in the maintenance of cellular redox homeostasis through several mechanisms. At the same time, GST enzyme causes the development of resistance, especially chemotherapeutic drugs. This development of resistance is associated with altered drug permeability and increased levels of Glutathione (GSH) and GST enzymes in the cell. Therefore, compounds or drug-like drugs that GSTs as their target are important for preclinical and clinical studies. In particular, molecular docking new ligands to a protein target by virtual screening efficiently represents drug metabolism enzymes. We hypothesized that inhibition of GST by selenourea and Etacrynic acid combination sensitizes breast cancer cells to apoptotic signaling by altering redox homeostasis, leading to the identification of specific apoptosis-cleaved proteins that drive cell death pathways. Methods: This study was carried out to demonstrate the binding and inhibition effect of selenourea compound to glutathione S-transferase enzymes (GSTs) for the structure-based design is the biggest obstacle. So, different GST enzyme sub-types of appropriate molecular docking were used. Also, we analyzed cell proliferation with MTS and protein expression with western blot analysis of combination therapy with selenourea and Etacrynic acid to target GST inhibition and revealed apoptosis-cleaved proteins in estrogen positive MCF7 cell and non-estrogenic MDA-MB-231breast cancer. Results: In the results, it was found that selenourea acts through targeting by indirect S-glutathionylation modification of cysteine residues in target proteins, although its polar covalent bond, hydrogen bond, and ionic interaction bind to other amino acids in all sub-types of GST. The combination of selenourea and etacrynic acid dose-dependently inhibited cell proliferation. Selenourea and Etacrynic acid combination exhibited important statistical difference in both cell p