Chemopreventive effect of fish oil derived EPA in lung cancer

鱼油衍生的 EPA 对肺癌的化学预防作用

基本信息

批准号：
8245134
负责人：
PEIYING YANG
金额：
$ 31.8万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8245134
关键词：
A/J Mouse A549 Adenocarcinoma Adverse effects Affect Animal Model Animals Arachidonic Acids Aspirin Benign Binding Biological Cancer Control Cancer Etiology Cancer Model Cardiotoxicity Cardiovascular system Cause of Death Cell Line Cessation of life Chemoprevention Chemopreventive Agent Colon Carcinoma Consumption Coxibs Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclooxygenase Inhibitors Data Development Diet Dinoprostone Docosahexaenoic Acids Dose EP4 receptor Eicosapentaenoic Acid Enzymes Epidemiologic Studies Epidermal Growth Factor Receptor Epithelial Cells FDA approved FVB Mouse Fish Oils Fishes Goals Growth Growth and Development function H1299 Heart Diseases Human Human Development In Vitro Incidence Indomethacin Inflammation Mediators Inflammatory Knockout Mice LOX gene Lesion Link Lung Lung Adenocarcinoma Lung Adenoma Lung Neoplasms MAP Kinase Gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Membrane Metabolism Methods Modeling Molecular Molecular Target Mus Mutation Non-Small-Cell Lung Carcinoma Non-Steroidal Anti-Inflammatory Agents Omega-3 Fatty Acids Pathway interactions Patients Peripheral Blood Mononuclear Cell Pharmacodynamics Pharmacologic Substance Phospholipids Polyunsaturated Fatty Acids Population Premalignant Prevention Prevention strategy Protein Array Relative (related person)Research Research Project Grants Risk Role Sampling Series Signal Pathway Signal Transduction Small Interfering RNA Smoker Structure of parenchyma of lung Supplementation Survival Rate Target Populations Testing Transgenic Mice Translating Tumor Tissue Up-Regulation Urethane Variant Western Blotting Woman Work anticancer activity base cancer cell cancer prevention cancer therapy carcinogenesis celecoxib cellular engineering chemotherapy cyclooxygenase 2 dietary supplements eicosanoid metabolism feeding high risk human WFDC2 protein improved in vivo inhibitor/antagonist insight lung cancer prevention lung carcinogenesis malignant breast neoplasm men neoplastic cell novel outcome forecast overexpression patient population phase 2 study pre-clinical prevent prostaglandin E3 prostaglandin EP2 receptor protective effect public health relevance receptor research clinical testing research study response smoking cessation treatment strategy tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the single greatest cause of death from malignancy in both men and women in the US, exceeding that of the next three combined leading ncers (prostate, colon and breast cancer). Although smoking cessation is a key to lung cancer prevention, it remains a challenge. Finding effective preventive and treatment strategies for lung cancer are desperately needed. Cyclooygenase-2 (COX-2), a key mediator of inflammation, is an important target for lung cancer therapy and prevention because approximately 70% of lung adenocarcinomas have overexpression of COX-2 and regular use of aspirin and other NSAIDs is associated with a reduced risk of developing lung cancer in animal models and smokers. Regardless of the cardiac toxicity of selective COX-2 inhibitors, a growing body of evidence supports the etiological impact of COX-2 in lung cancer. Fish oil represents an attractive series of n-3 fatty acids (eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids) that modulate COX-2 activity while having beneficial cardiovascular effects. The strong link between COX-2 and fish oil-induced chemoprevention has been strengthen by recent findings of high consumption of long chain n-3 fatty acids lowering their risk of prostate cancer and this protective effect being more pronounced in men carrying a particular COX-2 variant. The ultimate goal of this proposal is to define the optimal dose of EPA and relevant fish oil products to maximize the chemopreventive effects of fish oil against human lung cancer and to identify an appropriate molecular target of fish oil for prevention of lung cancer. We will determine the chemopreventive role of EPA and fish oils using a urethane- induced mouse lung cancer model with and without expression of COX-2, as well as the K-ras mutation mouse lung model. We will also evaluate the molecular mechanisms associated with EPA-induced tumor growth suppression by studying the biological effects of PGE2 and the EPA metabolite PGE3 in premalignant and lung cancer cells and their interaction with PGE2 receptors. The critical role of EPA-derived PGE3 in lung cancer prevention using the urethane-induced mouse lung cancer model with or without expression of EP receptor, particularly EP2 and EP4 receptors, will be further studied. This proposal intends to define a novel targeted natural chemopreventive agent against lung cancer. PUBLIC HEALTH RELEVANCE: The proposed research involves studies of fish oil-derived eicosapentaenoic acid (EPA) and pharmaceutical grade FDA approved fish oil product, which we hypothesize to be very effective for prevention of lung cancer development. Initial promising work using an in vivo mouse lung carcinogenesis model, which mimics the development of human adenocarcinoma, will be expanded to further identify the specific mechanisms of action of fish oil-derived n-3 fatty acids in lung cancer prevention. Given that fish oil has been widely accepted by US population as safe and has shown promise in inflammatory and cardiac diseases as well as possessing anticancer activity, the results from these studies will determine if sufficient promising data can be obtained to warrant clinical evaluation of this particular dietary supplement in high risk targeted populations with the goal of delaying or preventing the onset of lung cancer in this particular population.

描述（由申请人提供）：肺癌是美国男性和女性恶性肿瘤死亡的最大单一原因，超过了紧随其后的三种主要癌症（前列腺癌、结肠癌和乳腺癌）的总和。尽管戒烟是预防肺癌的关键，但它仍然是一个挑战。迫切需要寻找有效的肺癌预防和治疗策略。环合酶-2 (COX-2) 是炎症的关键介质，是肺癌治疗和预防的重要靶点，因为大约 70% 的肺腺癌过度表达 COX-2，并且定期使用阿司匹林和其他 NSAID 与肺癌的发生有关。降低动物模型和吸烟者患肺癌的风险。尽管选择性 COX-2 抑制剂具有心脏毒性，但越来越多的证据支持 COX-2 对肺癌的病因学影响。鱼油代表一系列有吸引力的 n-3 脂肪酸（二十碳五烯酸 (EPA) 和二十二碳六烯酸 (DHA) 酸），可调节 COX-2 活性，同时具有有益的心血管作用。最近发现大量摄入长链 n-3 脂肪酸可降低患前列腺癌的风险，并且这种保护作用在携带特定 COX-2 的男性中更为明显，这进一步加强了 COX-2 和鱼油诱导的化学预防之间的密切联系。 2 变体。该提案的最终目标是确定EPA和相关鱼油产品的最佳剂量，以最大限度地发挥鱼油对人类肺癌的化学预防作用，并确定鱼油预防肺癌的适当分子靶点。我们将使用氨基甲酸乙酯诱导的表达和不表达 COX-2 的小鼠肺癌模型以及 K-ras 突变小鼠肺癌模型来确定 EPA 和鱼油的化学预防作用。我们还将通过研究 PGE2 和 EPA 代谢物 PGE3 在癌前细胞和肺癌细胞中的生物学效应及其与 PGE2 受体的相互作用，评估与 EPA 诱导的肿瘤生长抑制相关的分子机制。将进一步研究 EPA 衍生的 PGE3 在使用乌拉坦诱导的小鼠肺癌模型（表达或不表达 EP 受体，特别是 EP2 和 EP4 受体）预防肺癌中的关键作用。该提案旨在定义一种针对肺癌的新型靶向天然化学预防剂。公共健康相关性：拟议的研究涉及鱼油衍生的二十碳五烯酸 (EPA) 和 FDA 批准的医药级鱼油产品的研究，我们假设该产品对于预防肺癌的发展非常有效。使用模拟人类腺癌发展的体内小鼠肺癌发生模型的初步有前途的工作将得到扩展，以进一步确定鱼油衍生的 n-3 脂肪酸在预防肺癌中的具体作用机制。鉴于鱼油已被美国民众广泛认为是安全的，并且在治疗炎症和心脏病以及具有抗癌活性方面显示出前景，这些研究的结果将决定是否可以获得足够的有希望的数据来保证对这种特殊的临床评估针对高风险目标人群的膳食补充剂，旨在延缓或预防该特定人群肺癌的发病。