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：
8467989
负责人：
PEIYING YANG
金额：
$ 29.89万
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8467989
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.

描述（由申请人提供）：肺癌是美国男性和女性的恶性死亡原因，超过了接下来的三个联合主要NCER（前列腺，结肠癌和乳腺癌）。尽管戒烟是预防肺癌的关键，但仍然是一个挑战。迫切需要寻找有效的肺癌预防和治疗策略。环氧酶-2（COX-2）是炎症的关键介体，是肺癌疗法和预防的重要靶标，因为大约70％的肺腺癌的肺腺癌过度表达了COX-2，并且定期使用阿司匹林和其他NSAID与动物模型和吸烟者中肺癌发展的风险降低有关。不管选择性COX-2抑制剂的心脏毒性如何，越来越多的证据支持COX-2对肺癌的病因影响。鱼油代表了一系列有吸引力的N-3脂肪酸（Eicosapentaenoic（EPA）和Docosahecahexaenoic（DHA）酸），可调节COX-2活性，同时具有有益的心血管效应。最近发现，长链N-3脂肪酸降低了前列腺癌的风险，COX-2与鱼油诱导的化学预防之间的牢固联系得到了加强，并且这种保护作用在携带特定Cox-2变体的男性中更为明显。该提案的最终目标是定义EPA和相关鱼油产品的最佳剂量，以最大程度地提高鱼油对人肺癌的化学预防作用，并确定鱼油的适当分子靶标，以预防肺癌。我们将使用氨基甲酸酯诱导的小鼠肺癌模型和具有COX-2表达的小鼠肺癌模型以及K-RAS突变小鼠肺模型来确定EPA和鱼油的化学预防作用。我们还将通过研究PGE2和EPA代谢产物PGE3在预抗癌前和肺癌细胞中的生物学作用以及它们与PGE2受体的相互作用来评估与EPA诱导的肿瘤生长抑制相关的分子机制。 EPA衍生的PGE3在使用氨基甲酸酯诱导的小鼠肺癌模型（或不表达EP受体，尤其是EP2和EP4受体的表达）中的关键作用将进一步研究。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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prostaglandin E3 metabolism and cancer.

DOI：
10.1016/j.canlet.2014.03.010
发表时间：
2014-06-28
期刊：
CANCER LETTERS
影响因子：
9.7
作者：
Yang, Peiying;Jiang, Yan;Fischer, Susan M.
通讯作者：
Fischer, Susan M.

Changes in cancer cell metabolism revealed by direct sample analysis with MALDI mass spectrometry.

DOI：
10.1371/journal.pone.0061379
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Pirman DA;Efuet E;Ding XP;Pan Y;Tan L;Fischer SM;DuBois RN;Yang P
通讯作者：
Yang P

Anticancer activity of fish oils against human lung cancer is associated with changes in formation of PGE2 and PGE3 and alteration of Akt phosphorylation.

DOI：
10.1002/mc.22008
发表时间：
2014-07
期刊：
MOLECULAR CARCINOGENESIS
影响因子：
4.6
作者：
Yang, Peiying;Cartwright, Carrie;Chan, Diana;Ding, Jibin;Felix, Edward;Pan, Yong;Pang, Jihai;Rhea, Patrea;Block, Keith;Fischer, Susan M.;Newman, Robert A.
通讯作者：
Newman, Robert A.

Deletion of cyclooxygenase-2 inhibits K-ras-induced lung carcinogenesis.