Elena Kalinina

Role of glutathione, glutathione transferase, and glutaredoxin in regulation of redox-dependent processes

Over the last decade fundamentally new features have been revealed for the participation of glutathione and glutathione-dependent enzymes (glutathione transferase and glutaredoxin) in cell proliferation, apoptosis, protein folding, and cell signaling. Reduced glutathione (GSH) plays an important role in maintaining cellular redox status by participating in thiol-disulfide exchange, which regulates a number of cell functions including gene expression and the activity of individual enzymes and enzyme systems. Maintaining optimum GSH/GSSG ratio is essential to cell viability. Decrease in the ratio can serve as an indicator of damage to the cell redox status and of changes in redox-dependent gene regulation. Disturbance of intracellular GSH balance is observed in a number of pathologies including cancer. Consequences of inappropriate GSH/GSSG ratio include significant changes in the mechanism of cellular redox-dependent signaling controlled both nonenzymatically and enzymatically with the participation of isoforms of glutathione transferase and glutaredoxin. This review summarizes recent data on the role of glutathione, glutathione transferase, and glutaredoxin in the regulation of cellular redox-dependent processes.

Expression of Peroxiredoxin 1, 2, 3, and 6 Genes in Cancer Cells during Drug Resistance Formation

We studied the expression of peroxiredoxin genes (PRDX1, PRDX2, PRDX3, and PRDX6) in human erythroleukemia K652, human breast carcinoma MCF-7, and human ovarian carcinoma SKOV-3 cells during cisplatin resistance development. It was found that drug resistance formation was accompanied by a significant increase in the expression of PRDX1, PRDX2, PRDX3, PRDX6 genes in all cancer cell strains, which confirms the important contribution of redox-dependent mechanisms into the development of cisplatin resistance of cancer cells.

Expression of genes of glutathione transferase isoforms GSTP1-1, GSTA4-4, and GSTK1-1 in tumor cells during the formation of drug resistance to cisplatin.

We studied the expression of genes encoding glutathione-S-transferase isoforms GSTP1-1, GSTA4-4, and GSTK1-1 during the development of the resistance of human erythroleukemia (K562), mammary adenocarcinoma (MCF-7) and ovary adenocarcinoma (SKOV-3) cells to cisplatin (CDDP). It was found that drug resistance development in all three strains of tumor cells is associated with signifi cant increase in hGSTP1 and hGSTA4 gene expression, whereas increased hGSTK1 gene expression was detected only in resistant K562/CDDP and MCF-7/CDDP cells.

GSH-Dependent Redox Regulation and Antioxidant Enzymes in the Formation of Resistance to Doxorubicin in K562 Human Erythroleukemia Cells

Specific changes of antioxidant enzymes during initiation and promotion stages are special value for the study of role and regulation of free radical processes in mechanisms of cancinogenesis for prevention and reversion of malignization. In addition, among factors controlling the balance of homeostasis and formation of cellular resistance to environment free radical processes play the important role due to the including into proliferation and apoptosis which is discussed currently as one of the key events in free radical concept of chemical carcinogenesis (1).

Redox-Dependent Expression of Genes Encoding NADPH Oxidase 5 and the Key Antioxidant Enzymes during Formation of Drug Resistance of Tumor Cells to Cisplatin

Expression of genes that plays a significant role in the control of cellular redox homeostasis was studied during the development of drug resistance of human ovarian adenocarcinoma SKOV-3 cells to cisplatin. It was found that the development of drug resistance was accompanied by enhanced expression of the genes encoding the key antioxidant enzymes (SOD2, CAT, GPX1, and HO-1) and transcription factor Nrf2, as well as reduced expression of the gene encoding NOX5 isoform of NADPH oxidase. The results testify to redox-dependent development of the adaptive antioxidant response as an important process in the mechanism of formation of resistance to cisplatin.