Glutathione and glutathione-dependent enzymes in cancer drug resistance

Genetic and biochemical evidence has demonstrated that glutathione and glutathione-dependent enzymes play a central role in cellular defence against toxic environmental agents. Modulation of cellular glutathione homeostasis can also have a profound effect on the sensitivity of cancer cells to a wide range of drugs used in chemotherapy. These effects are produced by multifactorial mechanisms that involve inactivation of toxic electrophiles by conjugation, modulation of cellular redox state, activation of drug transporter systems and regulation of cell signalling and repair pathways. New data demonstrating the importance of these pathways in cytoprotection and greater understanding of the mechanisms which regulate their function reveal a number of new targets for novel anti-cancer agents. It is critical, however, if these targets are to be exploited correctly that the dynamics of glutathione regulation are taken into account.