DISCOVERY AND EVALUATION OF NOVEL TRITERPENOID CHEMOPREVENTIVES IN A NEW COLON CA

新型三萜化学预防剂在新结肠 CA 中的发现和评价

• 批准号: 7545051
• 负责人: John James Letterio
• 金额: $ 7.84万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-18 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545051
• 关键词: 1-Phosphatidylinositol 3-Kinase; 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; Acute; Address; Adverse effects; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antihypertensive Agents; Antineoplastic Agents; Biological Factors; Biological Markers; Biology; Cancer Death Rates; Cancer Patient; Cancer cell line; Carcinoma; Cardiovascular Diseases; Cardiovascular system; Cells; Chemicals; Chemistry; Chemoprevention; Chemopreventive Agent; Chinese Herbs; Cholesterol; Class; Clinical; Clinical Research; Colon; Colon Carcinoma; Colonic Neoplasms; Communication; Communities; Couples; Cultured Cells; Data; Death Rate; Detection; Development; Diet; Disease; Doctor of Medicine; Dose; Drug Delivery Systems; Early Diagnosis; Employee Strikes; Enhancers; Enzymes; Epigenetic Process; Epithelial; Epithelial Cells; Esters; Evaluation; Event; Family; Future; Gastrointestinal tract structure; Gene Expression; Genes; Genetic Transcription; Genus Cola; Germination; Goals; Growth Factor; Hamartomatous Polyp; Heart Diseases; Human; Hydroxyprostaglandin Dehydrogenases; Imidazole; Immune; In Vitro; Infarction; Inflammation; Inflammatory; Institution; Intestinal Neoplasms; Intraperitoneal Injections; Janus kinase; Knowledge; Laboratories; Leucine Zippers; Link; Lymphocytic Infiltrate; MADH4 gene; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Modeling; Molecular; Mus; Mutagenesis; Mutation; Newly Diagnosed; Non-Steroidal Anti-Inflammatory Agents; Nuclear; Numbers; Oleanolic Acid; Oncogenic; Oral Administration; Oxidative Stress; PTGS2 gene; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Phenotype; Plant Roots; Pre-Clinical Model; Prevention; Primary carcinoma of the liver cells; Process; Property; Recurrence; Refractory; Research; Research Personnel; Risk; Role; STAT protein; STAT3 gene; Safety; Scientist; Serum; Signal Transduction; Signaling Molecule; Skeletal system; Skeleton; Source; Staging; Standards of Weights and Measures; Steroids; Stress; Structure-Activity Relationship; Syndrome; System; T-Lymphocyte; TNF gene; Techniques; Testing; Therapeutic; Time; Transforming Growth Factors; Translations; Tumor Suppressor Proteins; Universities; Vascular Endothelial Growth Factors; Woman; Work; anticancer research; bryonolic acid; cancer chemoprevention; cancer prevention; carcinogenesis; celecoxib; cyclooxygenase 2; cytokine; day; design; feeding; functional group; gastrointestinal; human NOS2A protein; improved; in vivo; inhibitor/antagonist; knock-down; knockout gene; lung Carcinoma; macrophage; men; mouse model; novel; novel therapeutics; oleanane; prevent; prototype; response; small molecule; small molecule libraries; transcription factor; tumor; tumor progression

DESCRIPTION (provided by applicant): The field of cancer chemoprevention represents a unique opportunity for the fruitful cooperation of basic scientists and clinical researchers to tackle a problem of acute need. One of the best examples to date of a potential cancer chemopreventive is the semisynthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), which was born out of a structure activity relationship (SAR) with the natural product oleanolic acid (from Chinese herbs). The proposed work described herein will expand our knowledge of triterpenoids as small molecule chemopreventives by focusing on bryonolic acid, a natural product abundantly produced in the roots of germinating Curcubita pepo L. (common zucchini). We aim to study the effect of this molecule on key inflammation-related markers of carcinogenesis and determine its potential as a pharmacologic chemopreventive with a special emphasis on colon cancer. To date we have devised a purification of this molecule yielding sub-gram quantities and illustrated its ability to inhibit the expression of iNOS and COX-2 in cell culture models. We are currently purifying multi-gram quantities of bryonolic acid and the goals of this proposal are centered on exploring the chemistry and biology of this molecule. Our two specific aims are: 1) to study the skeletal requirement of triterpenoid activity (for bryonolic acid and the entire triterpenoid family) using a diversity oriented synthesis (DOS) approach, and 2) determine whether triterpenoids are effective agents for the prevention of gastrointestinal carcinogenesis using cell culture and animal models. This proposal is strategically placed to potentially identify new chemopreventive agents which could be obtained from an abundant dietary source, but also to answer more fundamental questions about triterpenoids as chemopreventives. This project represents a collaborative endeavor between a synthetic organic chemist and a cancer biologist to address problems of cancer chemoprevention. The described aims will yield new molecules to be tested for their chemopreventive properties.

描述(申请人提供)：癌症化学预防领域是基础科学家和临床研究人员卓有成效地合作解决迫切需要的问题的独特机会。到目前为止，潜在的癌症化学预防的最好的例子之一是半合成的三萜类化合物2-氰基-3，12-二氧代油酸-1，9(11)-二烯-28-酸(CDDO)，它是从天然产物齐墩果酸(来自中药)的构效关系(SAR)中产生的。本文所描述的工作将扩展我们对三萜类化合物作为小分子化学保护剂的认识，重点关注苔藓酚酸，这是一种在萌发的西葫芦(Curcubita Pepo L.)根中大量产生的天然产物。我们的目标是研究这种分子对致癌的关键炎症相关标志物的影响，并确定其作为药物化学预防的潜力，特别是在结肠癌方面。到目前为止，我们已经设计了一种纯化该分子的方法，产生亚克量，并说明了它在细胞培养模型中抑制iNOS和COX-2表达的能力。我们目前正在提纯多克量的灯盏花酸，这项提议的目标是探索这种分子的化学和生物学。我们的两个具体目标是：1)利用面向多样性的合成(DOS)方法研究三萜类化合物(对灯盏花酸和整个三萜家族)的骨骼活性需求；2)通过细胞培养和动物模型确定三萜类化合物是否为预防胃肠道癌变的有效药物。这项建议的战略定位是潜在地寻找新的化学预防药物，这些药物可以从丰富的饮食来源中获得，但也回答了关于三萜类化合物作为化学预防药物的更基本的问题。这个项目代表了一位合成有机化学家和一位癌症生物学家之间的合作努力，以解决癌症化学预防的问题。所描述的AIMS将产生新的分子，以测试其化学预防特性。