Time-dependent and bidirectional effect of oxidative stress - a missing piece of the free radical theory of cancer and its potential implications

氧化应激的时间依赖性和双向效应——癌症自由基理论的缺失部分及其潜在影响

• 批准号: 9887609
• 负责人: Qingxia Chen
• 金额: $ 70.35万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9887609
• 关键词: 8-hydroxyguanosine; Accounting; Advanced Malignant Neoplasm; Aftercare; American; Animal Model; Antioxidants; Asians; Biochemical; Biological; Blood; Cancer Patient; Cancer Prognosis; Cancer Survivor; Chemoprevention; Chemopreventive Agent; Chinese People; Clinical; Cohort Studies; Colorectal Cancer; DNA; Development; Diagnostic; European; F2-Isoprostanes; Follow-Up Studies; Free Radicals; Health; Human; In Vitro; Intake; Joints; Lead; Link; Lipid Peroxidation; Longterm Follow-up; Malignant Neoplasms; Measurement; Measures; Molecular; Nature; Oncogenic; Oncologist; Outcome; Oxidative Stress; Participant; Patient Care; Patients; Phase; Pilot Projects; Population; Publishing; RNA; Radiation therapy; Randomized Clinical Trials; Research Personnel; Risk; Role; Sample Size; Sampling; Science; Supplementation; System; Target Populations; Time; Urine; Woman; Women' s Health; Work; cancer cell; cancer risk; cancer survival; carcinogenesis; cell injury; chemotherapy; cohort; colorectal cancer prevention; colorectal cancer risk; cytotoxic; design; diet and cancer; epidemiology study; follow-up; hazard; healing; insight; male health; novel; oxidation; oxidative damage; sex; theories; tumor; tumorigenesis

SUMMARY Conventional wisdom says that antioxidants should lower cancer risk by neutralizing cell- damaging, cancer-causing oxidative stress. However, despite the compelling biochemical evidence that ties oxidative damage to carcinogenesis for in vitro systems, almost all large randomized clinical trials have shown that antioxidant supplementation provides no clear benefit and even increases cancer risk. These disappointing and seemingly contradictory results have puzzled the public and researchers for decades. Even more controversial is whether antioxidant supplementation is safe and effective for cancer survivors. An estimated 15.5 million Americans in 2016 were cancer survivors, and up to 81% of them used antioxidant supplements to promote healing. However, we do not understand whether and to what extent post-treatment oxidative stress is associated with cancer prognosis. We recently conducted a molecular epidemiological study of colorectal cancer (CRC). We found the first piece of evidence in humans that the association between oxidative stress and CRC risk was bidirectional, with both beneficial and deleterious effects. Moreover, these bidirectional effects were time-dependent. Specifically, in earlier phases of cancer development, high oxidative stress was associated with increased risk of CRC, whereas in later phases, it was associated with decreased risk. Correspondingly, we found that the association between antioxidant intake and CRC risk was also time- dependent and varied by baseline oxidative stress. In the pilot study, we found that among patients with more advanced cancer, their systemic levels of oxidative stress were actually lower. Furthermore, cancer patients with higher post-treatment levels of oxidative stress had odds of living longer, after comprehensively adjusting for clinical parameters. In this proposed study, we will conduct a large case-cohort study, building upon three Asian and European cohorts to determine whether our novel findings—the time-dependent and bidirectional effects of oxidative stress and antioxidants on CRC, first observed in Chinese women (discovery phase)—can be replicated in both sexes and in different ethnic populations (replication phase). Comprehensive assessments of oxidative stress in pre-diagnostic urine samples will be performed. We will also conduct a follow-up study of CRC cases from whom both pre-diagnostic and post-treatment urine samples have been collected. We will examine whether higher levels of systemic post-treatment oxidative stress are associated with better CRC survival, while comprehensively accounting for pre-diagnostic oxidative stress and other clinical parameters. We expect that this study, with its focus on the time-dependent and bidirectional association between oxidative stress and CRC, will provide novel insights into the role of oxidative stress in carcinogenesis, the first evidence linking oxidative stress and clinical outcomes of CRC, and much needed information for identification of population subsets for chemoprevention. Thus, this study will have high translational potential to lead to tailored strategies for CRC prevention and patient care.

概括 传统观点认为，抗氧化剂应该通过中和细胞来降低癌症风险 然而，尽管有令人信服的生化证据表明，氧化应激具有破坏性、致癌性。 几乎所有大型随机临床试验都表明氧化损伤对体外系统的致癌作用 补充抗氧化剂没有明显的好处，甚至会增加癌症风险。 几十年来，令人失望且看似矛盾的结果一直困扰着公众和研究人员。 更有争议的是补充抗氧化剂对于癌症幸存者是否安全有效。 据估计，2016 年有 1550 万美国人是癌症幸存者，其中高达 81% 使用抗氧化剂 然而，我们不知道是否以及在何种程度上进行后治疗。 我们最近进行了一项分子流行病学研究。 我们在人类中发现了第一个证据表明结直肠癌（CRC）之间存在关联。 氧化应激和结直肠癌风险是双向的，既有有益的作用，也有有害的作用。 具体而言，在癌症发展的早期阶段，高氧化作用具有时间依赖性。 压力与结直肠癌风险增加相关，而在后期阶段，压力与结直肠癌风险降低相关。 相应地，我们发现抗氧化剂摄入量与结直肠癌风险之间也存在时间相关性。 在初步研究中，我们发现，在患有更多氧化应激的患者中，氧化应激水平具有依赖性并随基线氧化应激而变化。 晚期癌症，他们的全身氧化应激水平实际上较低。 综合调整后，治疗后氧化应激水平较高的人有可能活得更长 在这项拟议的研究中，我们将在三个基础上进行大型病例队列研究。 亚洲和欧洲队列来确定我们的新发现——时间依赖性和双向性 氧化应激和抗氧化剂对结直肠癌的影响，首次在中国女性中观察到（发现阶段）——可以 可以在不同性别和不同种族人群中复制（综合复制阶段）。 我们还将对诊断前尿液样本中的氧化应激进行评估。 对诊断前和治疗后尿样均已采集的结直肠癌病例的随访研究 我们将检查是否与较高水平的全身治疗后氧化应激相关。 具有更好的 CRC 存活率，同时综合考虑诊断前氧化应激和其他因素 我们期望这项研究重点关注时间依赖性和双向性。 氧化应激与结直肠癌之间的关联，将为氧化应激在结直肠癌中的作用提供新的见解。 致癌作用，将氧化应激与结直肠癌临床结果联系起来的第一个证据，也是急需的 因此，这项研究将具有高度的识别化学预防人群子集的信息。 转化潜力可为 CRC 预防和患者护理制定量身定制的策略。