Role of oxygen radicals in DNA damage and cancer incidence

Abstract

The development of cancer in humans and animals is a multistep process. The complex series of cellular and molecular changes participating in cancer development are mediated by a diversity of endogenous and exogenous stimuli. One type of endogenous damage is that arising from intermediates of oxygen (dioxygen) reduction - oxygen-free radicals (OFR), which attacks not only the bases but also the deoxyribosyl backbone of DNA. Thanks to improvements in analytical techniques, a major achievement in the understanding of carcinogenesis in the past two decades has been the identification and quantification of various adducts of OFR with DNA. OFR are also known to attack other cellular components such as lipids, leaving behind reactive species that in turn can couple to DNA bases. Endogenous DNA lesions are genotoxic and induce mutations. The most extensively studied lesion is the formation of 8-OH-dG. This lesion is important because it is relatively easily formed and is mutagenic and therefore is a potential biomarker of carcinogenesis. Mutations that may arise from formation of 8-OH-dG involve GC --> TA transversions. In view of these findings, OFR are considered as an important class of carcinogens. The effect of OFR is balanced by the antioxidant action of non-enzymatic antioxidants as well as antioxidant enzymes. Non-enzymatic antioxidants involve vitamin C, vitamin E, carotenoids (CAR), selenium and others. However, under certain conditions, some antioxidants can also exhibit a pro-oxidant mechanism of action. For example, beta-carotene at high concentration and with increased partial pressure of dioxygen is known to behave as a pro-oxidant. Some concerns have also been raised over the potentially deleterious transition metal ion-mediated (iron, copper) pro-oxidant effect of vitamin C. Clinical studies mapping the effect of preventive antioxidants have shown surprisingly little or no effect on cancer incidence. The epidemiological trials together with in vitro experiments suggest that the optimal approach is to reduce endogenous and exogenous sources of oxidative stress, rather than increase intake of anti-oxidants. In this review, we highlight some major achievements in the study of DNA damage caused by OFR and the role in carcinogenesis played by oxidatively damaged DNA. The protective effect of antioxidants against free radicals is also discussed.

Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases

“…ROS by altering the growth signals and gene expression cause continuous proliferation of cancer cells [127]. ROS can damage DNA by inducing base modifications, deletions, strand breakage, chromosomal rearrangements and hyper-and hypo-methylation of DNA [128].…”

Oxidative Stress and Skin Cancer: An Overview

“…The presence of unpaired electrons usually confers a considerable degree of reactivity upon a free radical. The radicals derived from oxygen represent the most important class of such species generated in living systems [6]. Skin contains antioxidant defenses, which nullify ROS including free radicals, but these defenses will be overwhelmed if the dose of UV light is high enough, and this result in free radical damage to cellular components such as proteins, lipids and DNA [7,8].…”

Reconvene and Reconnect the Antioxidant Hypothesis in Human Health and Disease

“…Since FR were accused as causal factors in a large number of diseases, these were sometimes referred as ''Free Radical Diseases''. Some of the important diseases and health issues in this category are cancer [61][62][63][64][65][66][67], cardiovascular diseases [68][69][70][71][72][73], atherosclerosis [74][75][76][77][78][79][80][81], neurological disorders [82][83][84][85][86], renal disorders [87][88][89][90], liver disorders [91][92][93], hypertension [50,94,95], rheumatoid arthritis [96,97], adult respiratory distress syndrome, auto-immune deficiency diseases [98,99], inflammation, degenerative disorders associated with aging [100][101][102][103], diabetes mellitus [104][105]…”