The role of oxidative stress in chemical carcinogenesis.

Abstract

Oxidative stress results when the balance between the production of reactive oxygen species (ROS) overrides the antioxidant capability of the target cell; oxidative damage from the interaction of reactive oxygen with critical cellular macromolecules may occur. ROS may interact with and modify cellular protein, lipid, and DNA, which results in altered target cell function. The accumulation of oxidative damage has been implicated in both acute and chronic cell injury including possible participation in the formation of cancer. Acute oxidative injury may produce selective cell death and a compensatory increase in cell proliferation. This stimulus may result in the formation of newly initiated preneoplastic cells and/or enhance the selective clonal expansion of latent initiated preneoplastic cells. Similarly, sublethal acute oxidative injury may produce unrepaired DNA damage and result in the formation of new mutations and, potentially, new initiated cells. In contrast, sustained chronic oxidative injury may lead to a nonlethal modification of normal cellular growth control mechanisms. Cellular oxidative stress can modify intercellular communication, protein kinase activity, membrane structure and function, and gene expression, and result in modulation of cell growth. We examined the role of oxidative stress as a possible mechanism by which nongenotoxic carcinogens may function. In studies with the selective mouse liver carcinogen dieldrin, a species-specific and dose-dependent decrease in liver antioxidant concentrations with a concomitant increase in ROS formation and oxidative damage was seen. This increase in oxidative stress correlated with an increase in hepatocyte DNA synthesis. Antioxidant supplementation prevented the dieldrin-induced cellular changes. Our findings suggest that the effect of nongenotoxic carcinogens (if they function through oxidative mechanisms) may be amplified in rodents but not in primates because of rodents' greater sensitivity to ROS. These results and findings reported by others support a potential role for oxidative-induced injury in the cancer process specifically during the promotion stage.ImagesFigure 5Figure 6Figure 9

Oral Administration of Dimethylarsinic Acid, a Main Metabolite of Inorganic Arsenic, in Mice Promotes Skin Tumorigenesis Initiated by Dimethylbenz(a)anthracene with or without Ultraviolet B as a Promoter.

“…[22][23][24] For example, benzoyl peroxide is known to promote and cause the progression of mouse skin tumorigenesis, 25) and its effects are considered to be due to ROS, e.g., benzoyloxyl radical and hydroxyl radi- All tumors greater than 2 mm in diameter were excised and then fixed with 10% buffered formalin. Histopathological evaluation of tumors induced by DMBA resulted in classification into four lesions as indicated above.…”

Manganese superoxide dismutase overexpression inhibits the growth of androgen-independent prostate cancer cells

“…Mitochondria are considered as the most important cellular source of ROS and may be susceptible to oxidative damage. ROS can modify cellular protein, lipid, and DNA, which results in altered functions of the cell (Klaunig et al, 1998). It has been reported that ROS, when present at high levels, may play a key role in the mechanisms of initiation and progression of disease such as carcinogenesis (Oberley and Buettner, 1979;Cerutti, 1985;Church et al, 1993;Zhong et al, 1996), and disease associated with aging (Orr and Sohal, 1994).…”

DNA Adduct 8-Hydroxydeoxyguanosine, a Novel Putative Marker of Prognostic Significance in Ovarian Carcinoma

“…These highly reactive molecules are generated continuously either by metabolism in ordinary redox reactions, mainly in mitochondria, or through exposure to exogenous stimuli such as infectious and inflammatory agents, pollutants, radiation, or alcohol. 1 Normally, these oxidants are balanced by a synthesis of various defensive proteins. However, if ROS production exceeds the capacity of detoxification systems, principally antioxidant enzymes, oxidative stress is said to occur.…”