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：
7591022
负责人：
XIANG-DONG WANG
金额：
$ 27.23万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-19 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7591022
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具有重要健康状况的微量营养素的作用好处。它似乎提供了防止广泛的上皮癌的保护，包括肺，前列腺，胃和结肠。但是，两种p-胡萝卜素干预试验的矛盾结果都在吸烟者中（使用高剂量的P-胡萝卜素和肺癌风险增加）与观察性流行病学研究表明含有类胡萝卜素的水果和蔬菜的饮食（但浓度低于干预措施研究）与肺癌的风险降低有关，以及番茄红素对肺的影响的矛盾结果动物研究中的致癌作用激励我们将注意力集中在补充番茄红素的剂量上，番茄红素的生物学活性以及番茄红素代谢与香烟烟雾的相互作用。这项研究的目的是了解可能的化学预防功效的机械基础在良好的肺癌发育和番茄红素的代谢途径下，番茄红素（及其代谢产物）使用雪貂模型的控制实验条件，该模型与人类高度相似。我们假设这一点 1）番茄红素（或其代谢产物）与预防（或促进）之间存在剂量依赖性关联暴露于致癌的雪貂中的恶性肺病变和恶性肺部病变； 2）番茄红素（或番茄红素代谢物）通过上调胰岛素样生殖因子结合蛋白-3（IGFBP-3）作为A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'-偶加酶的表达（类胡萝卜素的裂解酶）可以通过补充番茄红素和烟雾来改变。我们的具体目的是1）确定两种生理学中番茄红素（和丙糖酰糖酸）的有效性（低和中位数）以及血浆和组织水平的药理学（高）番茄红素（和apo-lo'-糖粉酸），烟雾诱导的氧化应激，DNA损伤以及肺前塑性病变和肿瘤的发育在致癌的，香烟暴露的雪貂中的形成； 2）检查IGFBP-3的诱导是否是番茄红素或其代谢产物抑制IGF-1和细胞增殖的信号转导途径，并促进雪貂和细胞培养模型的凋亡； 3）通过检查番茄红素的代谢途径胡萝卜素9'，lo'-单氧酶的表达和活性以及从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产物的生物活性。对于未来的人类研究而言，此信息至关重要预防肺癌和其他组织部位的癌症的番茄红素。此外，建立肺雪貂中的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。