Effect of the reduction of superoxide dismutase 1 and 2 or treatment with α-tocopherol on tumorigenesis in Atm-deficient mice
Effect of the reduction of superoxide dismutase 1 and 2 or treatment with α-tocopherol on tumorigenesis in Atm-deficient mice
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DOI：
10.1016/j.freeradbiomed.2006.04.032
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发表时间：
2006-08-15
影响因子：
7.4
通讯作者：
Wynshaw-Boris, Anthony
中科院分区：
文献类型：
--
作者：
Erker, Laura;Schubert, Ralf;Wynshaw-Boris, Anthony
ATM缺陷小鼠是人类疾病共济失调-毛细血管扩张的一种易患癌症的模型，表现出氧化应激和损伤水平的增加。用氮氧化物抗氧化剂和超氧化物歧化酶模拟物(4-hydroxy-2，2，6，6-tetramethylpiperidine-N-oxyl)慢性治疗这些小鼠，会导致肿瘤发生的潜伏期延长。我们最初的假设是，坦普尔的化学预防作用是由于它的超氧化物歧化酶模拟活性减少了细胞的氧化应激和损伤。然而，也有可能坦普尔的樱桃预防作用是由直接减轻超氧阴离子自由基诱导的氧化应激和损伤以外的机制造成的。为了帮助区分这些可能性，我们试图通过移除胞质SOD1或减少线粒体Sod2来在遗传上增加ATM缺陷小鼠的氧化应激，或者我们试图通过用α-生育酚治疗ATM缺陷小鼠来降低氧化应激。令人惊讶的是，我们发现同时减少ATM和Sod1或ATM和Sod2并没有缩短肿瘤形成的潜伏期，也没有显著影响寿命。此外，持续给予α-生育酚并不影响胸腺淋巴瘤的潜伏期。因此，从基因上降低ATM缺陷小鼠的超氧化物歧化酶或用α-生育酚治疗对存活率或肿瘤形成没有影响，这表明坦普尔的预防樱桃核损伤的作用可能至少部分独立于其减少氧化损伤和压力的作用。(C)2006 Elsevier Inc.保留所有权利。
Atm-deficient mice, a cancer-prone model of the human disease ataxia-telangiectasia, display increased levels of oxidative stress and damage. Chronic treatment of these mice with the nitroxide antioxidant and superoxide dismutase (SOD) mimetic Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) resulted in an increased latency to tumorigenesis. We initially hypothesized that the chemopreventative effect of Tempol was due to its SOD mimetic activity reducing cellular oxidative stress and damage. However, it is also possible that the chernopreventative effect of Tempol results from mechanisms other than directly reducing superoxide radical-induced oxidative stress and damage. To help distinguish between these possibilities, we attempted to genetically increase oxidative stress in Atm-deficient mice by either removing cytosolic Sod1 or reducing mitochondrial Sod2, or we attempted to decrease oxidative stress by treatment of Atm-deficient mice with alpha-tocopherol. Surprisingly, we found that reducing both Atm and Sod1 or Atm and Sod2 did not shorten latency to tumorigenesis or significantly affect life span. Furthermore, continuous administration of a-tocopherol did not affect latency to thymic lymphomas. Thus, genetically reducing Sod in Atm-deficient mice or treatment with alpha-tocopherol had no effect on survival or tumorigenesis, suggesting that the chernopreventative effect of Tempol may be at least partially independent of its effects on reducing oxidative damage and stress. (c) 2006 Elsevier Inc. All rights reserved.