Cancer chemoprevention by the antioxidant tempol in Atm-deficient mice.
Cancer chemoprevention by the antioxidant tempol in Atm-deficient mice.
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DOI：
10.1093/hmg/ddh189
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发表时间：
2004-08
影响因子：
3.5
通讯作者：
R. Schubert;Laura R. Erker;C. Barlow;H. Yakushiji;D. Larson;A. Russo;James B. Mitchell;A. Wynshaw-Boris
中科院分区：
文献类型：
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作者：
R. Schubert;Laura R. Erker;C. Barlow;H. Yakushiji;D. Larson;A. Russo;James B. Mitchell;A. Wynshaw-Boris
活性氧(ROS)是DNA损伤的重要内源性病原体，在细胞凋亡、应激反应和细胞增殖中发挥着重要的信号功能。食用高天然抗氧化剂饮食的人癌症发病率较低，与癌症组织中观察到的ROS增加之间的相关性表明，抗氧化剂可能用于癌症的化学预防。我们通过确定描述良好的氮氧化物抗氧化剂tempolTM是否在atm突变小鼠中起到化学预防作用来检验这一假设，atm突变小鼠是人类癌症倾向综合征共济失调-毛细血管扩张的模型。断奶后通过饮食持续给予temol可延长胸腺淋巴瘤的潜伏期，从而延长这些小鼠的寿命。坦普尔处理降低了ROS，恢复了线粒体膜电位，减少了组织氧化损伤和氧化应激，与抗氧化作用一致。此外，该氮氧化物在不改变摄食量、代谢或活动水平的情况下，降低了易患肿瘤的小鼠的体重增加，并在体外显示出抗增殖作用。因此，在这一人类癌症易发综合征的小鼠模型中，temol作为一种新的化学预防药物，与广泛的抗氧化作用有关。
Reactive oxygen species (ROS) are important endogenous etiological agents for DNA damage, and ROS perform critical signaling functions in apoptosis, stress responses and proliferation. The correlation between a lower incidence of cancer in people who consume a diet high in naturally occurring antioxidants and the observed increased ROS in cancerous tissues suggest that antioxidants may be used in cancer chemoprevention. We tested this hypothesis by determining whether the well-described nitroxide antioxidant, tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), acts as a chemopreventative agent in Atm mutant mice, a model of the human cancer prone syndrome ataxia-telangiectasia. Tempol administered continuously via the diet after weaning resulted in an increased lifespan of these mice by prolonging the latency to thymic lymphomas. Tempol treatment reduced ROS, restored mitochondrial membrane potential, reduced tissue oxidative damage and oxidative stress, consistent with antioxidant effects. In addition, this nitroxide lowered weight gain of tumor prone mice without changes in food intake, metabolism or activity level and exhibited an anti-proliferative effect in vitro. Thus, tempol acts as a novel chemopreventative agent in this mouse model of a human cancer prone syndrome, associated with broad antioxidant effects.