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. Environ Health Perspect 1 06(Suppl 1):289-295 (1998). http.//ehpnetl.niehs.nih.gov/docs/1998/Suppl-1/ 289-295klaunig/abstract.html

p38α limits the contribution of MAP17 to cancer progression in breast tumors

“…Furthermore, AKT activation may be involved in promoting survival of cells defective for p38 (Zuluaga et al, 2007) and in the increase of tumorigenic properties (Carnero, 2010). However, we suggest that other pathways induced by MAP17 could coexist at the transcriptional level, as has been described in other systems (Klaunig et al, 1998;Droge, 2002). In summary, MAP17 is a biomarker of malignant stages of breast tumors, in which it can enhance tumorigenic properties through ROS.…”

Loss of expression of chromosome 16q genes DPEP1 and CTCF in lobular carcinoma in situ of the breast

“…DPEP1 is also implicated in the metabolism of glutathione [30], an important antioxidant. If DPEP1 expression is reduced less glutathione is produced, increasing oxidative stress, which may increase carcinogenesis [31]. Although loss of expression of the novel gene DERPC has been found in renal and prostate tumours [21], no link has been found with breast cancer.…”

Induction of oxidative stress as a mechanism of action of chemopreventive agents against cancer

“…Reactive oxygen and nitrogen species are produced continuously by the mitochondria ( (Klaunig and Kamendulis, 2004;Genestra, 2007). During mitochondrial oxidative metabolism about 5% of oxygen is converted primarily into O 2 KÀ , whereas 95% of it is reduced to water.…”