Redox signaling and the emerging therapeutic potential of thiol antioxidants

Oxidation-reduction (redox) based regulation of signal transduction and gene expression is emerging as a fundamental regulatory mechanism in cell biology. Electron flow through side chain functional CH2-SH groups of conserved cysteinyl residues in proteins account for their redox-sensing properties. Because in most intracellular proteins thiol groups are strongly "buffered" against oxidation by the highly reduced environment inside the cell, only accessible protein thiol groups with high thiol-disulfide oxidation potentials are likely to be redox sensitive. The list of redox-sensitive signal transduction pathways is steadily growing, and current information suggests that manipulation of the cell redox state may prove to be an important strategy for the management of AIDS and some forms of cancer. The endogenous thioredoxin and glutathione systems are of central importance in redox signaling. Among the thiol agents tested for their efficacy to modulate cellular redox status, N-acetyl-L-cysteine (NAC) and alpha-lipoic acid hold promise for clinical use. A unique advantage of lipoate is that it is able to utilize cellular reducing equivalents, and thus it harnesses the metabolic power of the cell to continuously regenerate its reductive vicinal dithiol form. Because lipoate can be readily recycled in the cell, it has an advantage over N-acetyl-L-cysteine on a concentration:effect basis. Our current knowledge of redox regulated signal transduction has led to the unfolding of the remarkable therapeutic potential of cellular thiol modulating agents.