Role of reactive oxygen species in apoptosis: implications for cancer therapy

Reactive oxygen species are widely generated in biological systems. Consequ ently humans have evolved antioxidant defence systems that limit their prod uction. Intracellular production of active oxygen species such as (OH)-O-., O-2(-) and H2O2 is associated with the arrest of cell proliferation. Simil arly, generation of oxidative stress in response to various external stimul i has been implicated in the activation of transcription factors and to the triggering of apoptosis. Here we review how free radicals induce DNA seque nce changes in the form of mutations, deletions, gene amplification and rea rrangements. These alterations may result in the initiation of apoptosis si gnalling leading to cell death, or to the activation of several proto-oncog enes and/or the inactivation of some tumour suppressor genes. The regulatio n of gene expression by means of oxidants, antioxidants and the redox state remains as a promising therapeutic approach. Several anticarcinogenic agen ts have been shows to inhibit reactive oxygen species production and oxidat ive DNA damage, inhibiting tumour promotion. In addition, recombinant vecto rs expressing radical-scavenging enzymes reduce apoptosis. In conclusion, o xidative stress has been implicated in both apoptosis and the pathogenesis of cancer providing contrived support for two notions: free radical reactio ns may be increased in malignant cells and oxidant scavenging systems may b e useful in cancer therapy. (C) 2000 Published by Elsevier Science Ltd. All rights reserved.