HMG-CoA reductase inhibitor, tea polyphenols and pancreatic cancer prevention

HMG-CoA还原酶抑制剂、茶多酚与胰腺癌预防

• 批准号: 7257549
• 负责人: Guang-Yu Yang
• 金额: $ 12.08万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257549
• 关键词: Abbreviations; Address; Adenocarcinoma; Animal Model; Antibodies; Apoptosis; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Bile fluid; Binding; Biochemical; Biological Markers; Cancer Cell Growth; Cell Line; Cell Proliferation; Cells; Chemoprevention; Chemopreventive Agent; Cholesterol; Clinical; Coenzyme A; Data; Depth; Development; Dinoprostone; Dose; Ductal Epithelial Cell; Electrocardiogram; Epidemiologic Studies; Epigallocatechin Gallate; Event; Exhibits; Future; Gene Mutation; Genetically Engineered Mouse; Green tea; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hydroxymethylglutaryl-CoA reductase; Immunohistochemistry; In Vitro; Insulin-Like-Growth Factor I Receptor; JUN gene; K-ras Gene; K-ras Oncogene; Knock-in Mouse; Lamins; Lectin; Lesion; Link; Malignant neoplasm of pancreas; Membrane; Metabolic Pathway; Metastatic Neoplasm to the Liver; Modeling; Molecular; Molecular Models; Molecular Target; Mus; Mutation; Nuclear; Nuclear Lamin; Oxidoreductase; PTGS2 gene; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Phosphorylation; Preparation; Prevention; Prevention strategy; Principal Investigator; Production; Protein Isoprenylation; Proteins; Proto-Oncogene Proteins c-jun; Signal Transduction; Specimen; Stream; TP53 gene; Tea; Testing; Tobacco-Associated Carcinogen; Transformed Cell Line; Western Blotting; Yang; atorvastatin; base; breast intraductal proliferative lesion; cancer prevention; carcinogenesis; cyclooxygenase 2; design; driving force; epicatechin; epicatechin gallate; gallocatechol; geranylgeranyl pyrophosphate; glycosylation; human study; interest; intraepithelial; lung tumorigenesis; mevalonate; mouse model; mutant; p21 K-Ras Protein; polyphenol; prelamin A; prenylation; programs; ras Proteins; tumor

DESCRIPTION (provided by applicant): The objective of this project is to study the mechanism-based chemoprevention of pancreatic carcinogenesis by HMG-CoA reductase inhibitor Lipitor and its combination with polyphenol E (a standardized tea polyphenol preparation). Our central hypothesis is that the inhibition of K-ras oncogene-driven pancreatic carcinogenesis by Lipitor is through targeting the mevalonate metabolic pathway, in particular via inhibiting prenylation and dolichylation on k-ras, lamins and IGF-1R proteins; the synergistic or additive effects on prevention of pancreatic carcinogenesis by the combination of Lipitor and polyphenol E will be produced through inhibition of arachidonic acid metabolits and down-stream signals of the K-ras pathway (such as ErK1/2 and c-Jun protein phosphorylation). We will test this hypothesis using a genetically engineered mouse model of pancreatic cancer (compound endogenously and conditionally knocked-in mouse model: LSL-k- rasG12D/?Trigh doses, and combination with low dose, of each agent) to test whether the combination of agents produces synergistic or additive effects, in addition to the inhibitory effect of each agent on pancreatic carcinogenesis. 2. Test the hypothesis that targeting the mevalonate pathway, arachidonic acid metabolits, and K-ras downstream signals by the combination of Lipitor and polyphenol E are the key molecular mechanisms in the prevention of pancreatic carcinogenesis. The specimens generated from Specific Aim 1 will be further examined for activity of k-ras protein, Ras, and IGF-1R protein membranous bound, and k-ras downstream signals, lamin and arachidonic acid metabolites with the biochemical and immunochemical approaches to reveal the mechanism involved. Furthermore, in-depth mechanistic studies will be performed using the selected immortalized human pancreatic ductal epithelial cell line and its k-ras transformed cell line in vitro. Using a genetically engineered mouse model of molecular-mimic pancreas cancer combined with chemopreventive agents, this project will be significant in the development of efficient strategy for the prevention of pancreas cancer in human.

描述（申请人提供）：本项目的目的是研究HMG-CoA还原酶抑制剂立普妥及其与多酚E（一种标准化茶多酚制剂）的组合对胰腺癌发生的基于机制的化学预防。我们的中心假设是，立普妥抑制 K-ras 癌基因驱动的胰腺癌发生是通过靶向甲羟戊酸代谢途径，特别是通过抑制 k-ras、核纤层蛋白和 IGF-1R 蛋白上的异戊二烯化和多羟基化；立普妥与多酚E合用可通过抑制花生四烯酸代谢和K-ras通路下游信号（如ErK1/2和c-Jun蛋白磷酸化）产生协同或相加的预防胰腺癌作用。我们将使用胰腺癌基因工程小鼠模型（复合内源性条件性敲入小鼠模型：LSL-k-rasG12D/？每种药物的高剂量和低剂量组合）来测试这一假设，以测试除了每种药物对胰腺癌发生的抑制作用之外，药物组合是否产生协同或相加效应。 2. 验证立普妥与多酚 E 联合靶向甲羟戊酸途径、花生四烯酸代谢和 K-ras 下游信号是预防胰腺癌发生的关键分子机制的假设。具体目标1产生的样本将通过生化和免疫化学方法进一步检查k-ras蛋白、Ras和IGF-1R蛋白膜结合、k-ras下游信号、核纤层蛋白和花生四烯酸代谢物的活性，以揭示所涉及的机制。此外，将使用选定的永生化人胰腺导管上皮细胞系及其k-ras转化细胞系在体外进行深入的机制研究。该项目利用分子模拟胰腺癌的基因工程小鼠模型与化学预防药物相结合，对于制定预防人类胰腺癌的有效策略具有重要意义。