Schubert Ralf, Erker Laura, Barlow Carrolee, Yakushiji Hiroyuki, Larson Denise, Russo Angelo, Mitchell James B, Wynshaw-Boris Anthony
Department of Pediatrics, The Comprehensive Cancer Center, UCSD School of Medicine, La Jolla, CA 92093-0627, USA.
Hum Mol Genet. 2004 Aug 15;13(16):1793-802. doi: 10.1093/hmg/ddh189. Epub 2004 Jun 22.
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.
活性氧（ROS）是导致DNA损伤的重要内源性病因，并且ROS在细胞凋亡、应激反应和增殖过程中发挥关键的信号传导功能。食用富含天然抗氧化剂饮食的人群癌症发病率较低，以及在癌组织中观察到ROS增加，二者之间的相关性表明抗氧化剂可用于癌症化学预防。我们通过确定一种广为人知的氮氧化物抗氧化剂——Tempol（4-羟基-2,2,6,6-四甲基哌啶-N-氧化物）是否在Atm突变小鼠（一种人类易患癌症综合征共济失调-毛细血管扩张症的模型）中作为化学预防剂来验证这一假设。断奶后通过饮食持续给予Tempol可延长这些小鼠发生胸腺淋巴瘤的潜伏期，从而延长其寿命。Tempol治疗可降低ROS水平，恢复线粒体膜电位，减少组织氧化损伤和氧化应激，这与抗氧化作用一致。此外，这种氮氧化物可降低易患肿瘤小鼠的体重增加，而食物摄入量、新陈代谢或活动水平均无变化，并且在体外表现出抗增殖作用。因此，在这种人类易患癌症综合征的小鼠模型中，Tempol作为一种新型化学预防剂，具有广泛的抗氧化作用。
