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

Reactive oxygen species are widely generated in biological systems. Consequently humans have evolved antioxidant defence systems that limit their production. Intracellular production of active oxygen species such as (OH)-O-., O-2(-) and H2O2 is associated with the arrest of cell proliferation. Similarly, generation of oxidative stress in response to various external stimuli has been implicated in the activation of transcription factors and to the triggering of apoptosis. Here we review how free radicals induce DNA sequence changes in the form of mutations, deletions, gene amplification and rearrangements. These alterations may result in the initiation of apoptosis signalling leading to cell death, or to the activation of several proto-oncogenes and/or the inactivation of some tumour suppressor genes. The regulation of gene expression by means of oxidants, antioxidants and the redox state remains as a promising therapeutic approach. Several anticarcinogenic agents have been shows to inhibit reactive oxygen species production and oxidative DNA damage, inhibiting tumour promotion. In addition, recombinant vectors expressing radical-scavenging enzymes reduce apoptosis. In conclusion, oxidative stress has been implicated in both apoptosis and the pathogenesis of cancer providing contrived support for two notions: free radical reactions may be increased in malignant cells and oxidant scavenging systems may be useful in cancer therapy. (C) 2000 Published by Elsevier Science Ltd. All rights reserved.