Lycopene Chemoprevention of Lung Cancer in Ferret

番茄红素对雪貂肺癌的化学预防作用

• 批准号: 7036073
• 负责人: XIANG-DONG WANG
• 金额: $ 28.05万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 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/7036073
• 关键词: DNA damage; aerobiosis; apoptosis; binding proteins; biological signal transduction; cancer prevention; carcinogenesis; carcinogens; carotenoids; cell proliferation; chemoprevention; dietary supplements; disease /disorder model; enzyme activity; enzyme linked immunosorbent assay; ferrets; insulinlike growth factor; lung neoplasms; model design /development; oxidative stress; oxygenases; preneoplastic state; smoking; tissue /cell culture; tobacco

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）：越来越多的流行病学证据支持番茄红素作为一种具有重要健康益处的微量营养素的作用。它似乎可以预防多种上皮性癌症，包括肺癌、前列腺癌、胃癌和结肠癌。然而，对吸烟者进行的p-胡萝卜素干预试验（使用高剂量的p-胡萝卜素，肺癌风险增加）与观察性流行病学研究的结果相互矛盾，结果表明，饮食中含有大量类胡萝卜素的水果和蔬菜（但浓度远低于干预研究）与肺癌风险降低有关。而在动物实验中，番茄红素对肺癌发生作用的相互矛盾的结果促使我们关注番茄红素的补充剂量、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番茄红素（及其代谢物）在良好控制的实验条件下对肺癌发展可能的化学预防作用的机制基础和番茄红素的代谢途径，采用高度类似于人类的雪貂模型。我们假设：1)番茄红素（或其代谢物）与预防（或促进）暴露于烟雾、经致癌物处理的雪貂的癌前和恶性肺病变之间存在剂量依赖关系；2)番茄红素（或番茄红素代谢物）以上调胰岛素样生长因子结合蛋白-3 （IGFBP-3）为分子靶点，阻断IGF-I的信号转导通路，从而抑制肺癌的发生，是番茄红素发挥化学预防作用的机制；3)番茄红素的氧化代谢和胡萝卜素9′，10′-单加氧酶（类胡萝卜素的一种裂解酶）的表达均可因番茄红素的补充和烟雾暴露而改变。我们的具体目标是：1)确定番茄红素（和载脂蛋白o′-番茄红素酸）在生理（低和中）和药理学（高）剂量下对血浆和组织水平的番茄红素（和载脂蛋白o′-番茄红素酸）、烟雾诱导的氧化应激、DNA损伤、肺癌前病变的发展和肿瘤形成的有效性；2)在雪貂和细胞培养模型中，研究番茄红素或其代谢物诱导IGFBP-3是否抑制IGF-1信号转导通路和细胞增殖，促进细胞凋亡；3)在体内和体外研究番茄红素的代谢途径，检测胡萝卜素9′、lO′-单加氧酶的表达和活性，以及番茄红素形成载脂蛋白lO′-番茄红素。我们的研究将为番茄红素及其代谢物的生物活性机制提供重要的见解。这一信息对于未来涉及番茄红素预防肺癌和其他组织部位癌症的人类研究至关重要。此外，雪貂肺癌发生模型的建立为肺癌和类胡萝卜素的研究提供了有价值的工具。