The relationship between oxidative stress, antioxidants and cancer

• Main Author: Erker, Laura R
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2004
• Subjects: Genetics; Molecular biology; Oncology
• ISBN: 9780496140923; 0496140922

Elevated levels of oxidative stress are found in cancerous tissues, there is evidence that ROS are involved in cellular signaling and that elevated levels of ROS can lead to cellular transformation. There is also evidence that the reduction of intracellular ROS via antioxidant treatment may reverse ROS-mediated transformation and prevent cancer initiation, progression and/or maintenance. We tested this hypothesis by determining whether the nitroxide antioxidant and superoxide dismutase (SOD) mimetic, tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), acts as a chemopreventative agent in Atm-deficient mice, which display elevated levels of oxidative stress. Tempol administered via the diet resulted in an increased lifespan of Atm −/− mice by prolonging the latency to thymic lymphomas. Tempol reduced ROS, restored mitochondrial membrane potential, reduced tissue oxidative damage and stress, consistent with antioxidant effects. To further investigate the role of oxidative stress in tumorigenesis of Atm −/− mice, oxidative stress was genetically increased in Atm-deficient mice by producing mice that were deficient in Atm and either cytosolic Sod1 or mitochondrial Sod2. Atm-deficiency combined with Sod1 -deficiency or Sod2 reduction did not affect latency to tumorigenesis or tumor spectrum compared to Atm −/− mice, even though oxidative stress and protein damage were appreciably increased in tissues susceptible to tumors. Thus, genetically increasing the oxidative stress/damage displayed by Atm −/− mice has no detectable effect on tumorigenesis. This suggests that oxidative stress is not the only cause of cancer in Atm-deficient mice and that there may be other chemopreventative effects of tempol treatment besides the reduction of oxidative stress and damage in Atm-deficient mice. To test this, cancer prone p53 −/− mice, which do not display oxidative stress, were treated with tempol. Tempol treatment slightly but significantly increased the lifespan of these mice without any effect on oxidative damage or stress. Tempol treatment increased phosphorylation of p53 at ser18, a direct target of Atm and increased p21 protein expression in thymocytes. However, phosphorylation of γH2AX, another direct target of Atm, was not increased by tempol, demonstrating that tempol has specific effects on Atm mediated signaling pathways. Thus, tempol acts as a novel chemopreventative agent in two mouse models of human cancer prone syndromes. Chemoprevention, in part, is mediated by activation of the p53 pathway.