Lycopene Chemoprevention of Lung Cancer in Ferret

番茄红素对雪貂肺癌的化学预防作用

基本信息

批准号：
7908141
负责人：
XIANG-DONG WANG
金额：
$ 13.61万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7908141
关键词：
A549 Accounting Acids Address Affect Animal Experiments Animal Model Animals Apoptosis Apoptotic Attention Binding Proteins Biological Biological Markers CYP1A1 gene Cancer cell line Carcinogens Carotene Carotenoids Catabolism Cell Culture Techniques Cell Proliferation Cell Respiration Cells Chemoprevention Chemopreventive Agent Child Cigarette Cigarette Smoker Cleaved cell Colon Complement Conflict (Psychology)Cyclins Cytochrome P450 DNA Damage Development Diet Dietary Intervention Dose Effectiveness Enhancing Lesion Enzymes Epidemiologic Studies Epidemiology Epithelial Epithelial Cells Exogenous Factors Exposure to Ferrets Free Radicals Future Goals Health Benefit Human IGF-1 Signaling Pathway In Vitro Insulin Insulin-Like Growth Factor Binding Protein 3 Insulin-Like Growth Factor I Intake Intervention Studies Intervention Trial Investigation Lesion Lipid Peroxidation Liver Lung Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Metabolic Pathway Metabolism Micronutrients Mitogen-Activated Protein Kinases Mixed Function Oxygenases Modeling Molecular Molecular Target Nicotine Non-Small-Cell Lung Carcinoma Normal Cell Observational Study Organ Oxidative Stress Pathway interactions Phosphorylation Phosphotransferases Physiological Plasma Premalignant Prevention Property Prostate Regulation Research Retinoic Acid Receptor Risk Role Signal Transduction Signal Transduction Pathway Site Smoke Smoker Smoking Somatomedins Spouses Stomach Structure Structure of parenchyma of lung Study models Supplementation Tissues Tobacco Tobacco smoke Tomatoes Tretinoin Tumor Suppressor Proteins base cancer risk cancer type carcinogenesis cell transformation chemical carcinogen cigarette smoke-induced cigarette smoking dosage fruits and vegetables in vivo insight lung cancer prevention lung carcinogenesis lung development lycopene non-smoking oxidative DNA damage pi bond prevent protective effect response smoking cessation tobacco exposure tool tumor

项目摘要

Increasing epidemiological evidence supports the role of lycopene as a micronutrient with important health benefits. It appears to provide protection against a broad range of epithelial cancers, including lung, prostate, stomach and colon. However, both the conflicting results of the p-carotene intervention trials in cigarette smokers (which used high doses of p-carotene and increased lung cancer risk) vs. the observational epidemiological studies showing that diets high in fruits and vegetables containing carotenoids (but at much lower concentrations than in the intervention studies) are associated with a decreased risk for lung cancer, and the conflicting results of lycopene effects on lung carcinogenesis in animal studies motivate us to focus our attention on the dosage of lycopene supplementation, biological activities of lycopene and interaction of lycopene metabolism with cigarette smoke. The objective of this investigation is to understand the mechanistic basis for the possible chemopreventive efficacy of lycopene (and its metabolites) against lung cancer development and the metabolic pathway of lycopene under well- controlled experimental conditions, using the ferret model, which is highly analogous to humans. We hypothesize that 1) there is a dose-dependent association between lycopene (or its metabolites) and the prevention (or promotion) of premalignant and malignant lung lesions in smoke-exposed, carcinogen-treated ferrets; 2) lycopene (or lycopene metabolites) inhibit lung carcinogenesis by up-regulating insulin-likegrowth factor binding protein-3 (IGFBP-3) as a molecular target and interrupting the signal transduction pathway of IGF-I as a mechanism for the chemopreventive efficacy of lycopene; and 3) both oxidative metabolism of lycopene and expression of carotene 9',10'-monooxygenase (a cleavage enzyme for carotenoids) can be altered by lycopene supplementation and smoke-exposure. Our specific aims are 1) determine the effectiveness of lycopene (and apo-lO'-lycopenoic acid) in both physiologic (low and median) and pharmacological (high) doses on plasma and tissue levels of lycopene (and apo-lO'-lycopenoic acid), smoke-induced oxidative stress, DNA damage, and development of lung preneoplastic lesions and tumor formation in the carcinogen treated, cigarette smoke-exposed ferrets; 2) examine whether the induction of IGFBP-3 with lycopene or its metabolites inhibits the signal transduction pathway of IGF-1 and cell proliferation and promotes apoptosis in both ferret and cell culture models; and 3) investigate the metabolic pathway of lycopene by examining both the expression and activity of carotene 9', lO'-monooxygenase and the formation of apo-lO'-lycopenoids from lycopene in vivo and in vitro. Our research effort will provide important insights regarding the mechanisms leading to the bioactivity of lycopene and its metabolites. This information is critically needed for future human studiesinvolving lycopene for prevention of lung cancer and cancers at other tissue sites. In addition, the establishment of a lung carcinogenesis model in ferrets provides a valuable tool for both lung cancer and carotenoid research fields.

越来越多的流行病学证据支持番茄红素作为一种对健康具有重要意义的微量营养素的作用好处。它似乎可以预防多种上皮癌，包括肺癌、前列腺癌、胃癌和冒号。然而，对吸烟者进行的β-胡萝卜素干预试验（使用了高剂量的β-胡萝卜素会增加肺癌风险）与观察性流行病学研究表明饮食中富含类胡萝卜素的水果和蔬菜（但浓度比干预中低得多）研究）与降低肺癌风险有关，而番茄红素对肺癌的影响却是相互矛盾的结果动物研究中的致癌作用促使我们将注意力集中在番茄红素补充剂的剂量上，番茄红素的生物活性以及番茄红素代谢与香烟烟雾的相互作用。本研究的目的是了解可能的化学预防功效的机制基础番茄红素（及其代谢物）对肺癌发展的影响以及番茄红素在良好条件下的代谢途径使用与人类高度相似的雪貂模型控制实验条件。我们假设 1) 番茄红素（或其代谢物）和预防（或促进）之间存在剂量依赖性关联暴露于烟雾、接受致癌物质处理的雪貂的癌前和恶性肺部病变； 2）番茄红素（或番茄红素代谢物）通过上调胰岛素样生长因子结合蛋白-3 (IGFBP-3) 抑制肺癌发生分子靶标并中断 IGF-I 的信号转导途径作为化学预防的机制番茄红素的功效； 3)番茄红素的氧化代谢和胡萝卜素9',10'-单加氧酶的表达（类胡萝卜素的裂解酶）可以通过补充番茄红素和接触烟雾而改变。我们的具体目标是 1) 确定番茄红素（和 apo-10'-番茄红素酸）在生理学和生理学方面的有效性。 (低和中值)和药理学(高)剂量对番茄红素(和apo-10'-番茄红素)血浆和组织水平的影响酸）、烟雾诱导的氧化应激、DNA 损伤以及肺癌前病变和肿瘤的发展在经过致癌物处理、接触香烟烟雾的雪貂中形成； 2)检查是否诱导IGFBP-3 与番茄红素或其代谢物结合抑制IGF-1和细胞增殖的信号转导途径，促进雪貂和细胞培养模型中的细胞凋亡； 3）通过检查来研究番茄红素的代谢途径胡萝卜素 9'、10'-单加氧酶的表达和活性以及 apo-10'-番茄红素的形成番茄红素在体内和体外。我们的研究工作将提供有关导致机制的重要见解番茄红素及其代谢物的生物活性。这些信息对于未来的人类研究至关重要番茄红素用于预防肺癌和其他组织部位的癌症。此外，还建立了肺雪貂致癌模型为肺癌和类胡萝卜素研究领域提供了有价值的工具。