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：
7224877
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/7224877
关键词：
A549 Accounting Acids Address Affect Animal Experiments Animal Model Animals Apoptosis Apoptotic Attention BAD gene Bad protein Biological Biological Markers CYP1A1 gene Cancer cell line Carcinogens Carotene Carotenoids Catabolism Cell Proliferation Cell Respiration Cells Chemoprevention Chemopreventive Agent Child Cigarette Cigarette Smoker Cleaved cell Colon Complement Condition Conflict (Psychology)Cultured Cells Cyclins Cytochrome P450 DNA Damage Development Diet Dietary Intervention Dose Effectiveness Enhancing Lesion Enzymes Epidemiologic Studies Epithelial Epithelial Cells Exogenous Factors Exposure to Ferrets Free Radicals Future Genus Cola Goals Health Benefit Human IGF-1 Signaling Pathway In Vitro 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 Numbers Object Attachment Observational Study Organ Oxidative Stress Pathway interactions Phosphorylation Phosphotransferases Physiological Plasma Premalignant Prevention Property Prostate Range 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 day dosage fruits and vegetables human study in vivo insight lung cancer prevention lung carcinogenesis lung development lycopene non-smoking oxidative DNA damage prevent protective effect response smoking cessation tobacco exposure tool tumor

项目摘要

DESCRIPTION (provided by applicant): 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-like growth 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 studies involving 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.

描述（由申请人提供）：增加流行病学证据支持番茄红素作为具有重要健康益处的微量营养素的作用。它似乎提供了针对广泛的上皮癌的保护，包括肺，前列腺，胃和结肠。 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在动物研究中，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番茄红素（及其代谢产物）对肺癌发育的可能化学预防功效的机理基础，以及使用雪貂模型在良好控制的实验条件下，在良好的控制实验条件下，番茄红素的代谢途径，该模型高度类似于人类。我们假设1）番茄红素（或其代谢产物）与预防（或促进）在烟雾暴露，致癌的雪貂中存在剂量依赖性相关性； 2）通过上调胰岛素样生长因子结合蛋白-3（IGFBP-3）作为分子靶标，并中断IGF-1的信号传递途径，通过上调胰岛素样生长因子结合蛋白-3（IGFBP-3）来抑制肺癌发生，以抑制肺癌发生。 3）番茄红素的氧化代谢和胡萝卜素9'，10'-偶加酶（类胡萝卜素的裂解酶）的表达都可以通过补充番茄红素的补充和烟雾来改变。 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经过致癌的，烟雾烟雾的雪貂； 2）检查使用番茄红素或其代谢产物诱导IGFBP-3是否抑制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中的凋亡；和3）通过检查颈ot子的表达和活性9'，lo'-单氧酶以及体内番茄红素和体外体外的apo-lo'-糖苷的形成，研究番茄红素的代谢途径。我们的研究工作将提供有关导致番茄红素生物活性及其代谢产物的机制的重要见解。对于未来的人类研究，涉及预防肺癌和其他组织部位的癌症的未来人类研究需要此信息。此外，在雪貂中建立肺癌发生模型为肺癌和类胡萝卜素研究领域提供了有价值的工具。