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：
7752828
负责人：
Qing Jiang
金额：
$ 19.9万
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 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7752828
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学有重要影响。我们认为某些形式的维生素 E 是治疗结肠癌的极佳抗癌剂。维生素E由八个分子组成，即1-、2-、3-、4-生育酚和1-、2-、3-、4-生育三烯酚。其中，只有组织中维生素 E 的主要形式 1-生育酚 (1T) 得到了广泛研究，包括其对结肠癌的化学预防潜力，但结果令人失望。我们和其他人最近的研究表明，美国饮食中富含的 3-生育酚 (3T) 可能是比 1T 更好的抗癌剂。特别是，我们已经证明，在培养细胞和大鼠炎症模型中，3T（而非 1T）通过抑制环氧合酶 (COX) 催化的前列腺素 E2 具有抗炎特性。我们的初步数据表明，3T 比 1T 更有效地抑制 5-脂氧酶 (5-LOX) 催化的白三烯 B4 的形成。 3T 的一种新代谢物 13'-羧基苯酚在粪便中检测到大量，它是比 3T 更强的 COX 和 5-LOX 抑制剂。除了抗炎特性外，我们的初步数据表明，3T 可能通过调节鞘脂合成来抑制结肠癌细胞系的生长并诱导细胞凋亡。最近，一项研究报告称，富含 3T 的混合生育酚可抑制氧化偶氮甲烷诱导的结肠癌模型中异常隐窝病灶的形成。这一有趣的发现与我们的观察结果相结合，得出了目前的假设：3T 可通过抗炎作用和潜在的鞘脂调节等机制有效预防结肠癌。该假设将通过追求以下具体目标来检验：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作用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) 在结肠炎相关结肠癌模型中检查 3T 和 1T 的抗癌作用，并研究观察到的作用背后的机制。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点，并为未来的人类临床研究提供重要的临床前数据。公共健康相关性：拟议的研究将提供强有力的证据，证明γ-生育酚（美国饮食中维生素 E 的主要形式）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。