Inhibition of peroxynitrite-mediated DNA strand cleavage and hydroxyl radical formation by aspirin at pharmacologically relevant concentrations: Implications for cancer intervention |
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Authors: | Wei Chen Hong Zhu Jianrong Li Kequan Zhou Yunbo Li |
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Institution: | a Division of Biomedical Sciences, Edward Via Virginia College of Osteopathic Medicine, Virginia Tech Corporate Research Center, Blacksburg, VA 24060, USA b College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310035, China c Department of Food Science and Technology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA d Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA |
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Abstract: | Epidemiological studies have suggested that the long-term use of aspirin is associated with a decreased incidence of human malignancies, especially colorectal cancer. Since accumulating evidence indicates that peroxynitrite is critically involved in multistage carcinogenesis, this study was undertaken to investigate the ability of aspirin to inhibit peroxynitrite-mediated DNA damage. Peroxynitrite and its generator 3-morpholinosydnonimine (SIN-1) were used to cause DNA strand breaks in φX-174 plasmid DNA. We demonstrated that the presence of aspirin at concentrations (0.25-2 mM) compatible with amounts in plasma during chronic anti-inflammatory therapy resulted in a significant inhibition of DNA cleavage induced by both peroxynitrite and SIN-1. Moreover, the consumption of oxygen caused by 250 μM SIN-1 was found to be decreased in the presence of aspirin, indicating that aspirin might affect the auto-oxidation of SIN-1. Furthermore, EPR spectroscopy using 5,5-dimethylpyrroline-N-oxide (DMPO) as a spin trap demonstrated the formation of DMPO-hydroxyl radical adduct (DMPO-OH) from authentic peroxynitrite, and that aspirin at 0.25-2 mM potently diminished the radical adduct formation in a concentration-dependent manner. Taken together, these results demonstrate for the first time that aspirin at pharmacologically relevant concentrations can inhibit peroxynitrite-mediated DNA strand breakage and hydroxyl radical formation. These results may have implications for cancer intervention by aspirin. |
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Keywords: | DMPO 5 5-dimethylpyrroline-N-oxide DMPO-OH DMPO-hydroxyl adduct DMPO-OOH DMPO-superoxide spin adduct EPR electron paramagnetic resonance SOD superoxide dismutase ROS reactive oxygen species SIN-1 3-morpholinosydnonimine |
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