Chen Wei, Zhu Hong, Jia Zhenquan, Li Jianrong, Misra Hara P, Zhou Kequan, Li Yunbo
Division of Biomedical Sciences, Edward Via Virginia College of Osteopathic Medicine, Virginia Tech Corporate Research Center, Blacksburg, VA 24060, USA.
Biochem Biophys Res Commun. 2009 Dec 4;390(1):142-7. doi: 10.1016/j.bbrc.2009.09.083. Epub 2009 Sep 26.
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 phiX-174 plasmid DNA. We demonstrated that the presence of aspirin at concentrations (0.25-2mM) 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 microM 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 0.25-2mM 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.
流行病学研究表明，长期使用阿司匹林与人类恶性肿瘤发病率降低有关，尤其是结直肠癌。由于越来越多的证据表明过氧亚硝酸盐在多阶段致癌过程中起关键作用，因此进行了本研究以调查阿司匹林抑制过氧亚硝酸盐介导的DNA损伤的能力。用过氧亚硝酸盐及其生成剂3-吗啉代 sydnonimine（SIN-1）在phiX-174质粒DNA中引起DNA链断裂。我们证明，在慢性抗炎治疗期间，阿司匹林浓度（0.25-2mM）与血浆中的量相当，可显著抑制过氧亚硝酸盐和SIN-1诱导的DNA裂解。此外，发现在阿司匹林存在下，250 microM SIN-1引起的氧气消耗减少，表明阿司匹林可能影响SIN-1的自动氧化。此外，使用5,5-二甲基吡咯啉-N-氧化物（DMPO）作为自旋捕获剂的EPR光谱表明，从真实的过氧亚硝酸盐形成了DMPO-羟基自由基加合物（DMPO-OH），并且0.25-2mM的阿司匹林以浓度依赖的方式有效地减少了自由基加合物的形成。综上所述，这些结果首次证明药理学相关浓度的阿司匹林可以抑制过氧亚硝酸盐介导的DNA链断裂和羟基自由基的形成。这些结果可能对阿司匹林的癌症干预有影响。
