Gamma-tocopherol as an effective anticancer agent for colon cancer

描述(由申请人提供)： 结肠癌是美国癌症死亡的第二大原因。慢性炎症是结肠癌发生的重要原因。我们认为某些形式的维生素E是治疗结肠癌的优秀抗癌药物。维生素E由8个分子组成，1-，2-，3-，4-生育酚和1-，2-，3-，4-生育三烯酚。其中，只有维生素E在组织中的主要形式1-生育酚(1T)被广泛研究，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，3-生育酚(3T)是一种比1T更好的抗癌剂，它在美国饮食中含量丰富。特别是，我们已经证明了3T而不是1T通过在培养细胞和大鼠炎症模型中抑制环氧合酶(COX)催化的前列腺素E2而具有抗炎特性。我们的初步数据显示，3T比1T更有效地抑制5-脂氧合酶(5-LOX)催化的白三烯B4的形成。在粪便中检测到大量的3T，13‘-羧基氯甘醇的一种新的代谢物，对Coxs和5-LOX的抑制作用比3T更强。除了抗炎作用外，我们的初步数据表明，3T可能通过调节鞘磷脂的合成来抑制结肠癌细胞系的生长和诱导其凋亡。最近，一项研究报道，富含3T的混合生育酚能抑制偶氮甲烷诱导的结肠癌模型中异常隐窝病灶的形成。这一耐人寻味的发现与我们的观察一起导致了目前的假设，即3T通过包括抗炎作用和鞘磷脂潜在调节在内的机制有效地预防结肠癌。这一假说将通过追求以下具体目标来验证：1)通过抗炎机制研究3T和1T的抗血管生成作用；2)研究鞘磷脂的潜在调节作用及其与3T介导的抗结肠癌细胞株增殖和促凋亡作用的相关性；以及3)在结肠炎相关性结肠癌模型中检测3T和1T的抗癌作用，并探讨其作用机制。这些研究将阐明3T的新的抗癌机制，潜在地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。与公众健康相关：这项拟议的研究将提供强有力的证据，证明美国饮食中维生素E的主要形式--γ-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。

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.