Dual actions involved in arsenite-induced oxidative DNA damage.

Arsenic is a recognized human carcinogen, but the mechanism of carcinogenesis is not well understood. Oxidative stress and inhibition of DNA damage repair have been postulated as potential carcinogenic actions of arsenic. The present study tests the hypothesis that arsenite not only induces oxidative stress but also inhibits the activity of the DNA base excision repair protein, poly(ADP-ribose) polymerase-1 (PARP-1), leading to exacerbation of the oxidative DNA damage induced by arsenic. HaCat cells were treated with arsenite for 24 h before measuring 8-hydroxyl-2'-deoxyguanosine (8-OHdG), PARP-1 activity, and reactive oxygen species (ROS). Zinc supplementation and PARP-1 siRNA were used to increase or decrease, respectively, the PARP-1 protein's physiological function. At high concentrations (10 microM or higher), arsenite greatly induced oxidative DNA damage, as indicated by 8-OHdG formation. At lower concentrations (1 microM), arsenite did not produce detectable 8-OHdG, but was still able to effectively inhibit PARP-1 activity. Zinc supplementation reduced the formation of 8-OHdG, restored the PARP-1 activity inhibited by arsenite, but did not decrease ROS production. SiRNA knockdown of PARP-1 did not affect the 8-OHdG level induced by arsenic, while it greatly increased the 8-OHdG level produced by hydrogen peroxide indicating that PARP-1 is a molecular target of arsenite. Our findings demonstrate that in addition to inducing oxidative stress at higher concentrations, arsenite can also inhibit the function of a key DNA repair protein, PARP-1, even at very low concentrations, thus exacerbating the overall oxidative DNA damage produced by arsenite, and potentially, by other oxidants as well.

Low concentration of arsenite exacerbates UVR-induced DNA strand breaks by inhibiting PARP-1 activity.

Epidemiological studies have associated arsenic exposure with many types of human cancers. Arsenic has also been shown to act as a co-carcinogen even at low concentrations. However, the precise mechanism of its co-carcinogenic action is unknown. Recent studies indicate that arsenic can interfere with DNA-repair processes. Poly(ADP-ribose) polymerase (PARP)-1 is a zinc-finger DNA-repair protein, which can promptly sense DNA strand breaks and initiate DNA-repair pathways. In the present study, we tested the hypothesis that low concentrations of arsenic could inhibit PAPR-1 activity and so exacerbate levels of ultraviolet radiation (UVR)-induced DNA strand breaks. HaCat cells were treated with arsenite and/or UVR, and then DNA strand breaks were assessed by comet assay. Low concentrations of arsenite (

Protection of multiple antioxidants Chinese herbal medicine on the oxidative stress induced by adriamycin chemotherapy.

Adriamycin is an effective anthracycline anti-tumor antibiotic. However, the clinical use of adriamycin has been restricted by its serious side effects. Some reports indicated that the side effects of adriamycin could cause systemic injury, in which reactive oxygen species (ROS) play an important role. ROS are a large family of oxygen free radical and non-free radical active oxygen-containing molecules, including superoxide radical, hydrogen peroxide and hydroxyl radical, which contribute to oxidative stress. Although antioxidant treatment is a promising method to prevent the side effects, protection by a single antioxidant is limited. The Chinese herbal medicine ANTIOXIN is a multiple antioxidant that can effectively block oxidative stress. It was hypothesized that ANTIOXIN could effectively reduce the side effects of adriamycin. A rat tumor model with a transplanted tumor in the liver was treated with adriamycin and ANTIOXIN was used as a protection. Oxidative stress and antioxidant enzymes were evaluated. The results showed that adriamycin chemotherapy increased the level of malondialdehyde (MDA), nitrogen oxide (NO) and decreased the activities of total superoxide dismutase (T-SOD), manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione (GSH) and total antioxidant capacity (TAC). Adriamycin chemotherapy also decreased the expression of Bcl-2, increased the expression of iNOS and cell apoptosis in the liver and kidney. Multiple antioxidants ANTIOXIN had an antagonistic effect on these changes and significantly decreased the mortality of the experimental rats. These data demonstrated that adriamycin chemotherapy could cause oxidative stress to the whole body, on which multiple antioxidants based on the theory of 'multiple antioxidant chain' had effective protection.