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）：环氧酶（COX：COX-1/-2）和5-脂氧合酶（5-LOX）催化反应在结肠癌进展中起着重要作用。 cox抑制剂包括布洛芬，称为非甾体抗炎药（NSAID），已被证明是针对结肠癌的有效抗癌药。但是，使用这些酶的特定抑制剂的关键障碍是相关的不良反应，包括胃毒性和增加COX抑制剂心血管疾病的风险。因此，我们需要寻找具有强大抗癌作用并有可能降低毒性的新的预防和治疗策略。我们最近证明，维生素E形式在内，包括3-生育酚（3T），4托罗酚（4T）和3-苯甲醇（3TE）的维生素形式被代谢为长链羧基流酚及其在人类和大鼠中的长链羧基杂质及其硫酸对应物。重要的是，含有13碳长度的羧化侧链的E代谢物13'-carboxychromanol（13'-COOH）是一种有效的Cox-1/-2竞争抑制剂，其效力类似于布洛芬，而3T，4T和3TE和3TE或3TE或3TE或SHORTER链盒弹枪盒盒的型号非常弱。我们的初步数据表明，13'-COOH还抑制了5-lox催化的白细胞B4（LTB4）。双重抑制COX和5-LOX不仅可能导致更有效的抗炎和抗癌作用（通过抑制多种促炎途径），而且还可能降低由蛛网膜代谢中的分流引起的潜在不利影响，从而降低任何途径。因此，我们假设13'-COOHS可能是出色的抗癌药。该假设将通过追求细胞培养和动物研究中的以下特定目的来检验：1）研究4-13'-COOH（13'-COOH（13'-COOH）在结肠上皮细胞中4-13'-COOH（13'-COOH）的活性，并阐明了5-lox by-clox by-clox by-coby tyzanc和2）的机制。在小鼠模型中的4-13'-COOH，其中结肠癌的发生由甲氧甲烷（AOM）诱导，并通过硫酸葡萄糖硫酸钠（DSS）的结肠炎症加速。 4-13'-COOH的功效将与其未代谢前体4T和常用的NSAID布洛芬进行比较。还将研究4-13'-COOH在长期补充期间的生物利用度和潜在的不利影响。拟议的研究可能会发现一类新的有效抗癌剂，即长链羧基动物学，它们可能比NSAIDS和维生素E形式更有效，并且由于其独特的特性而显示出很少的不利影响。这些研究将把基于机制的发现扩展并转化为临床相关的癌症模型，并获得人类临床研究的重要临床前数据。 公共卫生相关性：环加氧酶和5-脂氧合酶催化的反应对结肠癌的发展产生显着贡献。我们最近证明，长链羧基胆醇（是新型维生素E代谢产物）有效抑制环氧酶 - 和5-脂氧合酶介导的反应。该应用是为了研究结肠癌细胞中的长链羧基酚和小鼠结肠癌模型中的抗癌活性。这些研究可能会发现具有潜在毒性低的有效抗癌剂，将扩展并将基于机制的发现扩展和转化为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临床前数据。