The Role of a Novel Vitamin E Metabolite in Colon Cancer Prevention and Therapy

新型维生素 E 代谢物在结肠癌预防和治疗中的作用

• 批准号: 8099210
• 负责人: Qing Jiang
• 金额: $ 20.1万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099210
• 关键词: A549; Adverse effects; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antineoplastic Agents; Apoptosis; Arachidonate 5-Lipoxygenase; Azoxymethane; Biological Availability; Cancer Etiology; Cancer Model; Carbon; Cell Culture Techniques; Cell Death; Cell Line; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chemopreventive Agent; Clinical Research; Colitis; Colon; Colon Carcinoma; Cultured Cells; Cyclooxygenase Inhibitors; Data; Development; Dinoprostone; Eicosanoids; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzyme Kinetics; Epithelial Cells; Exhibits; Future; Human; Ibuprofen; Immune system; Inflammation; Inorganic Sulfates; LOX gene; Length; Leukotriene B4; Leukotrienes; Malignant Neoplasms; Mediating; Metabolism; Modeling; Mus; Nature; Pathway interactions; Pharmaceutical Preparations; Play; Prevention; Property; Prostaglandin-Endoperoxide Synthase; Rat-1; Rattus; Reaction; Relative (related person); Rest; Role; Shunt Device; Side; Sodium Dextran Sulfate; Supplementation; System; Testing; Therapeutic; Tocopherols; Tocotrienols; Toxic effect; Translating; Unspecified or Sulfate Ion Sulfates; Vitamin E; Vitamins; anticancer activity; arachidonate; base; cancer cell; cancer prevention; cancer therapy; carboxylate; cardiovascular disorder risk; clinically relevant; colon cancer cell line; colon carcinogenesis; cyclooxygenase 1; human data; in vivo; inhibitor/antagonist; mouse model; novel; pre-clinical; tumor; tumor progression

DESCRIPTION (provided by applicant): Cyclooxygenases (COXs: COX-1/-2) and 5-lipoxygenase (5-LOX) catalyzed reactions play significant roles in colon cancer progression. COX inhibitors including ibuprofen, known as non-steroid anti- inflammatory drugs (NSAIDs), have been shown to be effective anticancer agents against colon cancer. However, a critical barrier to utilize the specific inhibitors of these enzymes is associated adverse effects including gastrotoxicity and increased risk of cardiovascular diseases for COX inhibitors. Therefore, we need to search for new prevention and therapeutic strategies that have strong anti-cancer effects with potentially reduced toxicity. We have recently demonstrated that vitamin E forms including 3-tocopherol (3T), 4-tocopherol (4T) and 3-tocotrienol (3TE) are metabolized to long-chain carboxychromanols and their sulfated counterparts in human cells and in rats. Importantly, 13'-carboxychromanol (13'-COOH), the E metabolite containing 13-carbon-length carboxylated side chain, is a potent competitive inhibitor of COX-1/-2 with the potency similar to ibuprofen, while 3T, 4T and 3TE or shorter-side chain carboxychromanols are much weaker COX inhibitors. Our preliminary data indicate that 13'-COOH also inhibited 5-LOX catalyzed leukotriene B4 (LTB4). The dual inhibition of COXs and 5-LOX may not only result in more potent anti-inflammatory and anti-cancer effect (by inhibiting multiple proinflammatory pathways), but may also reduce potential adverse effect caused by a shunt in arachidonate metabolism to either pathway. Therefore, we hypothesize that 13'-COOHs may be excellent anticancer agents. This hypothesis will be tested by pursuit of the following Specific Aims in cell culture and animal studies:1) investigate anti-inflammatory and anticancer activity of 4-13'-COOH (a 13'-COOH derived from 4-tocopherol) in colon epithelial cells and elucidate the mechanism underlying the inhibition of 5-LOX by enzyme kinetics, and 2) investigate in vivo anti-cancer activity of 4-13'-COOH in a mouse model, in which colon carcinogenesis is induced by azoxymethane (AOM) and is accelerated by dextran sulfate sodium (DSS)-caused colon inflammation. The efficacy of 4-13'-COOH will be compared with its unmetabolized precursor 4T and a commonly used NSAID, ibuprofen. The bioavailability and potential adverse effects of 4-13'-COOH during long-term supplementation will also be investigated. The proposed studies may discover a new class of effective anticancer agents, i.e., long-chain carboxychromanols, which may be more effective than NSAIDs and vitamin E forms, and exhibit few adverse effects due to their unique properties. These studies will extend and translate mechanism- based findings to a clinically relevant cancer model and obtain important preclinical data for human clinical studies. PUBLIC HEALTH RELEVANCE: Cyclooxygenases and 5-lipoxygenase catalyzed reactions contribute significantly to the development of colon cancer. We have recently demonstrated that long-chain carboxychromanols, which are novel vitamin E metabolites, potently inhibit cyclooxygenases- and 5-lipoxygenase-mediated reactions. This application is to investigate the anticancer activities of a long-chain carboxychromanol in colon cancer cells and in a colon cancer model in mice. These studies may discover a new class of effective anticancer agents with potentially low toxicity, will extend and translate mechanism-based findings to a clinically relevant animal model, and will gather necessary preclinical data important to human clinical studies.

描述（由申请人提供）：环加氧酶（COX：COX-1/-2）和5-脂加氧酶（5-LOX）催化的反应在结肠癌进展中发挥重要作用。包括布洛芬在内的 COX 抑制剂（称为非类固醇抗炎药 (NSAID)）已被证明是对抗结肠癌的有效抗癌药物。然而，利用这些酶的特定抑制剂的一个关键障碍是相关的副作用，包括 COX 抑制剂的胃毒性和心血管疾病风险增加。因此，我们需要寻找新的预防和治疗策略，具有强大的抗癌作用，同时可能降低毒性。我们最近证明，维生素 E 形式，包括 3-生育酚 (3T)、4-生育酚 (4T) 和 3-生育三烯酚 (3TE)，在人体细胞和大鼠体内代谢为长链羧基苯并二氢吡喃醇及其硫酸化对应物。重要的是，13'-羧基苯并二氢吡喃醇 (13'-COOH) 是一种含有 13 个碳长度的羧化侧链的 E 代谢物，是 COX-1/-2 的有效竞争性抑制剂，其效力与布洛芬相似，而 3T、4T 和3TE 或更短侧链的羧基苯并二氢吡喃醇是较弱的 COX 抑制剂。我们的初步数据表明，13'-COOH 还抑制 5-LOX 催化的白三烯 B4 (LTB4)。 COX 和 5-LOX 的双重抑制不仅可以产生更有效的抗炎和抗癌作用（通过抑制多种促炎途径），还可以减少花生四烯酸代谢分流到任一途径而引起的潜在不利影响。因此，我们假设13'-COOHs可能是优秀的抗癌剂。该假设将通过在细胞培养和动物研究中追求以下具体目标来检验：1) 研究 4-13'-COOH（源自 4-生育酚的 13'-COOH）在结肠上皮中的抗炎和抗癌活性细胞并阐明酶动力学抑制 5-LOX 的机制，2) 在小鼠模型中研究 4-13'-COOH 的体内抗癌活性，其中结肠氧化偶氮甲烷 (AOM) 会诱导癌变，而硫酸葡聚糖钠 (DSS) 引起的结肠炎症会加速癌变。 4-13'-COOH 的功效将与其未代谢的前体 4T 和常用的 NSAID 布洛芬进行比较。还将研究长期补充期间 4-13'-COOH 的生物利用度和潜在不利影响。拟议的研究可能会发现一类新的有效抗癌药物，即长链羧基苯并二氢吡喃醇，它可能比非甾体抗炎药和维生素 E 形式更有效，并且由于其独特的性质而几乎没有副作用。这些研究将基于机制的研究结果扩展并转化为临床相关的癌症模型，并为人类临床研究获得重要的临床前数据。 公共卫生相关性：环加氧酶和 5-脂加氧酶催化反应对结肠癌的发展有显着影响。我们最近证明，长链羧基苯并二氢吡喃醇是一种新型维生素 E 代谢物，可有效抑制环氧合酶和 5-脂氧合酶介导的反应。该应用旨在研究长链羧基苯并二氢吡喃醇在结肠癌细胞和小鼠结肠癌模型中的抗癌活性。这些研究可能会发现一类具有潜在低毒性的新型有效抗癌药物，将基于机制的发现扩展到临床相关的动物模型，并将收集对人类临床研究重要的必要的临床前数据。