Gamma-tocopherol as an effective anticancer agent for colon cancer

γ-生育酚作为结肠癌的有效抗癌剂

基本信息

批准号：
7580180
负责人：
Qing Jiang
金额：
$ 16.58万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7580180
关键词：
Aberrant crypt foci Action Potentials Angiogenesis Inhibitors Angiogenic Factor Animal Model Anti-Inflammatory Agents Anti-inflammatory Antineoplastic Agents Apoptosis Arachidonate 5-Lipoxygenase Azoxymethane Biochemical Cancer Etiology Cancer Model Cell Death Cessation of life Chemoprevention Chronic Clinical Research Colitis Colon Carcinoma Cultured Cells Cyclooxygenase Inhibitors Data Development Diet Dihydrosphingosine Dinoprostone Drug Delivery Systems Etiology Feces Future Goals Growth Human Inflammation Lead Leukotriene B4 Malignant Neoplasms Malignant neoplasm of prostate Mediating Modeling Molecular Target Play Prevention Prevention therapy Property Prostaglandin-Endoperoxide Synthase Rattus Reaction Reporting Role Sodium Dextran Sulfate Sphingolipids Testing Therapeutic Agents Tissues Tocopherols Tocotrienols Translating United States Vitamin E Vitamins angiogenesis antiangiogenesis therapy base cancer cell cancer prevention clinically relevant colon cancer cell line desaturase dihydroceramide disorder prevention gamma-Tocopherol human disease mouse model pre-clinical public health relevance tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Colon cancer is the second leading cause of cancer deaths in the United States. Chronic inflammation contributes significantly to the etiology of colon cancer development. We propose that certain forms of vitamin E are excellent anti-cancer agents for colon cancer. Vitamin E comprises eight molecules, 1-, 2-, 3-, 4-tocopherol and 1-, 2-, 3-, 4-tocotrienol. Among them, only 1-tocopherol (1T), the predominant form of vitamin E in tissues, has been extensively studied including its chemoprevention potential for colon cancer, but the results are disappointing. Recent studies by us and others indicate that 3-tocopherol (3T), which is rich in US diets, may be a much better anticancer agent than 1T. In particular, we have shown that 3T but not 1T has anti-inflammatory properties by inhibition of cyclooxygenase (COX)-catalyzed prostaglandin E2 in cultured cells and in a rat inflammation model. Our preliminary data showed that 3T more potently inhibits 5-lipoxygnease (5-LOX)-catalyzed formation of leukotriene B4 than 1T. A new metabolite of 3T, 13'-carboxychormanol, which is detected in significant amounts in feces, is an even stronger inhibitor of COXs and 5-LOX than 3T. In addition to the anti-inflammatory properties, our preliminary data indicated that 3T may inhibit growth and induce apoptosis in colon cancer cell lines by modulation of sphingolipid synthesis. Recently, a study reported that mixed tocopherols, which are enriched in 3T, inhibited aberrant crypt foci formation in azoxymethane-induced colon cancer model. This intriguing finding together with our observations leads to the current hypothesis that 3T is effective in prevention against colon cancer via mechanisms including anti-inflammatory action and potential modulation of sphingolipids. This hypothesis will be tested by pursuit of the following Specific Aims: 1) Investigate anti-angiogenic effect of 3T and 1T via the anti-inflammatory mechanism; 2) investigate potential modulation of sphingolipids and its relevance to 3T-mediated antiproliferation and pro-apoptosis effect in colon cancer cell lines; and 3) Examine anti-cancer effects of 3T and 1T in a colitis-associated colon cancer model, and investigate the mechanisms underlying the observed effects. These studies will elucidate new anti-cancer mechanisms of 3T, potentially identify a new drug target for colon cancer and provide important preclinical data for future human clinical studies. PUBLIC HEALTH RELEVANCE: The proposed study will provide strong evidence that gamma-tocopherol, the major form of vitamin E in US diet, is an effective chemoprevention and therapeutic agent for colon cancer. These studies will also provide biochemical mechanisms and important preclinical data for future human clinical studies.

描述（由申请人提供）：结肠癌是美国癌症死亡的第二大原因。慢性炎症对结肠癌发展的病因产生了重大贡献。我们建议某些形式的维生素E是结肠癌的出色抗癌药。维生素E包含八个分子，1-，2-，3-，4-生育酚和1-，2-，3-，4-苯酚。其中，只有1-生育酚（1T）是组织中维生素E的主要形式，包括其化学预防潜力的结肠癌潜力，但结果令人失望。我们和其他人的最新研究表明，富含美国饮食的3托生酚（3T）可能比1T更好。特别是，我们已经表明，通过抑制环氧酶（COX）催化的前列腺素E2在培养的细胞和大鼠炎症模型中，3T但不是1T具有抗炎特性。我们的初步数据表明，3T更有效地抑制5-脂透明酶（5-lox）催化白细胞B4的形成比1T。一种新的3T，13'-羧基chormanol的代谢产物，在粪便中大量检测到，比3T更强。除了抗炎特性外，我们的初步数据还表明，3T可以通过调节鞘脂合成来抑制生长并诱导结肠癌细胞系的凋亡。最近，一项研究报告说，在3T中富集的混合生育酚抑制了甲氧基甲烷诱导的结肠癌模型中的异常隐窝灶。这一有趣的发现以及我们的观察结果导致了当前的假设，即3T通过包括抗炎作用和鞘脂的潜在调节机制有效预防结肠癌。该假设将通过追求以下特定目的来检验：1）通过抗炎机制研究3T和1T的抗血管生成作用； 2）研究鞘脂的潜在调节及其与结肠癌细胞系中3T介导的抗增殖和促凋亡作用的相关性； 3）检查3T和1T在与结肠炎相关的结肠癌模型中的抗癌作用，并研究观察到的作用的基础机制。这些研究将阐明3T的新抗癌机制，有可能确定结肠癌的新药物靶标，并为未来的人类临床研究提供重要的临床前数据。公共卫生相关性：拟议的研究将提供有力的证据，表明美国饮食中维生素E的主要形式伽马生育酚是结肠癌的有效化学预防和治疗剂。这些研究还将为未来的人类临床研究提供生化机制和重要的临床前数据。