Cellular thiols and reactive oxygen species in drug-induced apoptosis

In higher eukaryotes, reactive oxygen species (ROS) are generated during re spiration in mitochondria in the course of reduction of molecular oxygen as well as by distinct enzyme systems. ROS have been implicated in the regula tion of diverse cellular functions including defense against pathogens, int racellular signaling, transcriptional activation, proliferation, and apopto sis. The reduction-oxidation (redox) state of the cell is primarily a conse quence of the precise balance between the levels of ROS and endogenous thio l buffers present in the cell, such as glutathione and thioredoxin, which p rotect cells from oxidative damage. Dramatic elevation of ROS, exceeding co mpensatory changes in the level of the endogenous thiol buffers, may result in the sustained activation of signaling pathways and expression of genes that induce apoptosis in affected cells. Many cytotoxic drugs function sele ctively to kill cancer cells by the abrogation of proliferative signals, le ading to cell death, and numerous reports have demonstrated that ROS are ge nerated following treatment with these drugs. In this review, we will summa rize recent contributions to our understanding of the importance of cytotox ic drug-induced modulation of cellular redox status for signaling and trans cription leading to activation of apoptotic effector mechanisms.