Molecular Mechanisms of Chemoprevention: NRF2 Signaling

化学预防的分子机制：NRF2 信号传导

• 批准号: 8228086
• 负责人: THOMAS W KENSLER
• 金额: $ 48.66万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228086
• 关键词: Abbreviations; Acetylcysteine; Aflatoxin B1; Aflatoxins; Alanine Transaminase; Animal Model; Anticarcinogenic Agents; Antioxidants; Biochemical; Biological; Biological Assay; Biological Markers; Biological Models; Blood; Cancer Burden; Carcinogens; Cell Survival; Chemicals; Chemoprevention; Chemopreventive Agent; Clinical Trials; DNA; Development; Dose; Embryo; Environmental Carcinogens; Epoxy Compounds; Equilibrium; Experimental Models; Exposure to; Feces; Fibroblasts; Gene Expression Profile; Genes; Genetic; Glutathione; Glutathione S-Transferase; Goals; Guanine; Hepatitis B; Hepatitis B Virus; Hepatocarcinogenesis; Human; Imidazole; Immunohistochemistry; Inbred F344 Rats; Individual; Intervention; Investigation; Isothiocyanates; Isotopes; Lead; Lesion; Leukotriene B4; Lipopolysaccharides; Liquid substance; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Mass Spectrum Analysis; Measures; Modeling; Molecular; Molecular Mechanisms of Action; Monitor; Mus; Mutation; Mycotoxins; NF-E2-related factor 2; NF-kappa B; NQO1 gene; Oligonucleotides; Oncogenes; Oxidoreductase; Pathway interactions; Plasma; Predictive Value; Primary carcinoma of the liver cells; Property; Protective Agents; Quinones; Radioisotope Dilution Technique; Rattus; Response Elements; Risk; Risk Factors; Role; Safety; Signal Pathway; Signal Transduction; Solid; Specimen; Sulforaphane; Thiones; Time; Toxic Environmental Substances; Translations; Urine; Validation; Work; adduct; aflatoxin B1 aldehyde reductase; aflatoxin-albumin adduct; base; cancer prevention; carcinogenesis; cost; dithiolethione; exposed human population; novel; oltipraz; protective effect; public health relevance; response; small molecule; tissue regeneration; tissue repair; transcription factor; Abbreviations; Acetylcysteine; Aflatoxin B1; Aflatoxins; Alanine Transaminase; Animal Model; Anticarcinogenic Agents; Antioxidants; Biochemical; Biological; Biological Assay; Biological Markers; Biological Models; Blood; Cancer Burden; Carcinogens; Cell Survival; Chemicals; Chemoprevention; Chemopreventive Agent; Clinical Trials; DNA; Development; Dose; Embryo; Environmental Carcinogens; Epoxy Compounds; Equilibrium; Experimental Models; Exposure to; Feces; Fibroblasts; Gene Expression Profile; Genes; Genetic; Glutathione; Glutathione S-Transferase; Goals; Guanine; Hepatitis B; Hepatitis B Virus; Hepatocarcinogenesis; Human; Imidazole; Immunohistochemistry; Inbred F344 Rats; Individual; Intervention; Investigation; Isothiocyanates; Isotopes; Lead; Lesion; Leukotriene B4; Lipopolysaccharides; Liquid substance; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Mass Spectrum Analysis; Measures; Modeling; Molecular; Molecular Mechanisms of Action; Monitor; Mus; Mutation; Mycotoxins; NF-E2-related factor 2; NF-kappa B; NQO1 gene; Oligonucleotides; Oncogenes; Oxidoreductase; Pathway interactions; Plasma; Predictive Value; Primary carcinoma of the liver cells; Property; Protective Agents; Quinones; Radioisotope Dilution Technique; Rattus; Response Elements; Risk; Risk Factors; Role; Safety; Signal Pathway; Signal Transduction; Solid; Specimen; Sulforaphane; Thiones; Time; Toxic Environmental Substances; Translations; Urine; Validation; Work; adduct; aflatoxin B1 aldehyde reductase; aflatoxin-albumin adduct; base; cancer prevention; carcinogenesis; cost; dithiolethione; exposed human population; novel; oltipraz; protective effect; public health relevance; response; small molecule; tissue regeneration; tissue repair; transcription factor

DESCRIPTION (provided by applicant): Cancer prevention involving reduction or elimination of human exposure to environmental carcinogens may not always be possible. Inhibition of the development of cancer by the administration of anticarcinogenic agents may offer practical alternatives for reducing human cancer burden. However, the successful utilization of chemopreventive interventions will require solid mechanistic understanding of the action(s) of these agents. We have identified the Keap1-Nrf2-ARE signaling pathway as a target for chemoprevention. The Nrf2 transcription factor regulates an integrated cell survival response that can be triggered by multiple classes of cancer chemopreventive agents (e.g., dithiolethiones, isothiocyanates, triterpenoids). In this project, we will use both pharmacologic and genetic approaches to further probe the molecular mechanisms of action of these chemopreventive agents, assess their efficacy in animal models with close relevance to human carcinogenesis and use these interventions to validate intermediate biomarkers. With a continuing focus on the roles of infection with hepatitis B virus and co-exposure to the fungal toxin aflatoxin on human risk for hepatocellular carcinoma, we will purse three aims. First, we will utilize advanced methods of isotope-dilution mass spectrometry for the quantitation of aflatoxin biomarkers in liver, blood, urine and feces in order to develop for the first time a comprehensive mass balance for the fate of the ultimate carcinogen, exo-aflatoxin-epoxide, in rats. The predictive value of these biomarkers for individual risk of liver cancer will be assessed. Biomarkers will be quantified longitudinally during a bioassay for protection against hepatocarcinogenesis by the exceptionally potent triterpenoid activator of Nrf2 signaling, CDDO-Im. We will also evaluate the predictive value of monitoring DNA circulating in plasma for mutations in target oncogenes using quantitative short oligonucleotide mass spectrometry. In the second aim, we will evaluate the similarities and distinctions of chemical class, species and genetic activation of Keap1-Nrf2 signaling by comparing the gene expression patterns in rat and mouse liver following treatment with lead compounds of 3 different chemical classes of Nrf2 activators at doses equi-effective for inhibition of aflatoxin-induced preneoplastic lesions and by comparing the gene expression patterns in liver of mice in which either Nrf2 or its repressor Keap1 have been genetically disrupted. The impact of these genetic and pharmacologic interventions on aflatoxin disposition will be determined using the mass spectrometry-based analysis of its biomarkers. Third, we will capitalize on our novel observation that Nrf2 signaling influences tissue regeneration and repair by examining the post initiation effects of triterpenoids during aflatoxin-induced hepatocarcinogenesis in the rat and in a murine model recapitulating major human risk factors for HCC, namely, aflatoxin exposure and infection with HBV. Collectively, these studies will further the goal of effectively using activators of Nrf2 signaling as protective agents in human populations exposed to environmental toxicants. PUBLIC HEALTH RELEVANCE: Cancer prevention involving reduction or elimination of human exposure to environmental carcinogens may not always be possible. The overriding goal of our work remains to provide the mechanistic framework to facilitate the efficient translation of the most effective of the small molecule activators of Nrf2 signaling into use as protective agents in human populations exposed to environmental toxicants such as aflatoxins. To facilitate this goal we need better understanding of the molecular mechanisms of action of our chemopreventive agents, further validation of intermediate biomarkers, and assessment of efficacy in animal models with close relevance to human carcinogenesis.

描述（由申请人提供）：预防癌症，涉及减少或消除人类对环境致癌物的暴露，可能并不总是可能。通过抗癌剂的给药抑制癌症的发育可能会提供减轻人类癌症负担的实际替代方法。然而，成功利用化学干预措施将需要对这些药物的作用进行牢固的机械理解。我们已经确定KEAP1-NRF2-ARE信号通路是化学预防的靶标。 NRF2转录因子调节了综合细胞存活反应，该反应可以由多种类别的癌症化学预防剂（例如二硫代硫代，异硫氰酸酯，三萜）触发。在该项目中，我们将使用药理学和遗传学方法进一步探测这些化学预防剂的作用分子机制，评估其在动物模型中与人类致癌物密切相关的动力，并使用这些干预措施来验证中间生物标志物。持续着重于丙型肝炎病毒感染的作用，并共同暴露于真菌毒素黄曲霉毒素对肝细胞癌的人类风险上的接触，我们将为三个目标。首先，我们将利用同位素稀释质谱的先进方法来定量肝脏，血液，尿液和粪便中的黄曲霉毒素生物标志物，以便首次发展为最终致癌物的命运，外生 - 富氟二氧素 - pepepoxide的命运。这些生物标志物对肝癌风险的预测价值将得到评估。生物标志物将在生物测定期间纵向量化，以防止NRF2信号传导CDDO-IM的特殊有效的三萜激活剂来防止肝癌发生。我们还将使用定量短寡核苷酸质谱法评估血浆中对目标致癌基因突变的DNA循环的预测值。在第二个目标中，我们将通过比较KEAP1-NRF2信号的化学类别，物种和遗传激活的相似性和区别，通过比较与3种不同化学品的NRF2激活剂的铅化合物在剂量上进行抑制rataToxin诱导的培养基的表达，并在剂量上比较3种不同化学品的NRF2激活剂的铅化合物的基因表达模式，并通过对这种剂量的表达进行比较。 NRF2或其阻遏物KEAP1在遗传上破坏了。这些遗传和药理干预措施对黄曲霉毒素处置的影响将使用基于质谱的生物标志物分析确定。第三，我们将利用我们的新颖观察结果，即NRF2信号传导通过检查黄曲霉毒素诱导的大鼠肝癌发生的三萜类化的启动效应，并在鼠模型中，将HCC的主要人类风险因素重新构成HCC的主要人类风险因素，即在HCCC中，Inflatoxin曝光，n.aflatoxin tabosure and Inflotection和HBV。总的来说，这些研究将进一步有效地使用NRF2信号传导的激活因子作为暴露于环境毒物的人群中的保护剂。 公共卫生相关性：预防癌症涉及减少或消除人类对环境致癌物的暴露，可能并不总是可能。我们工作的压倒性目标仍然是提供机械框架，以促进NRF2信号传导最有效的小分子激活剂的有效翻译，以用作暴露于环境有毒物质（例如黄曲霉毒素）的人群中的保护剂。为了促进这一目标，我们需要更好地理解化学预防剂的作用分子机制，进一步验证中间生物标志物，并评估与人类癌变密切相关的动物模型中的疗效。