Colon Cancer Inhibition by a Class of PPARgamma Agonists

一类 PPARgamma 激动剂对结肠癌的抑制作用

基本信息

批准号：
7546660
负责人：
Stephen H. Safe
金额：
$ 22.63万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7546660
关键词：
2,4-thiazolidinedione Accounting Adenomatous Polyposis Coli Adenomatous Polyps Adverse effects Age Agonist Apoptosis Cancer Cell Growth Cancer Center Cancer Etiology Cancer cell line Caveolins Cell Line Cells Cessation of life Chemoprevention Clinical Research Clinical Trials Collaborations Colon Colon Carcinoma Colonic Neoplasms Colorectal Cancer Critical Pathways Cyclin D1 Cytotoxic agent Developed Countries Developing Countries Development Diet Dietary Factors Differentiation Antigens Disease Doctor of Medicine Drug Combinations Drug Delivery Systems E-Cadherin Environmental Risk Factor Exhibits Fluorouracil Future Gene Proteins Genes Genetic Predisposition to Disease Germ-Line Mutation Goals Growth HT29 Cells Hereditary Nonpolyposis Colorectal Neoplasms Incidence Individual Indoles Inherited Inhibition of Cancer Cell Growth Intestinal Polyps Juvenile polyposis syndrome Laboratories Levamisole Link MADH4 gene MLH1 gene Mismatch Repair Molecular Mus Mutation Nomads Nude Mice Operative Surgical Procedures PPAR gamma PTEN gene Pathway interactions Peroxisome Proliferator-Activated Receptors Peutz-Jeghers Syndrome Pharmaceutical Preparations Pharmacologic Substance RNA Interference Research Personnel Retroviral Vector Role STK11 gene Series Structure Syndrome Testing Thiazolidinediones Toxic effect Toxicology Transactivation Transforming Growth Factors Transgenic Organisms Woman Xenograft Model Xenograft procedure analog base cancer cell cancer therapy caveolin 1 cdc Genes colon cancer cell line comparative diindolylmethane in vivo insight lifetime risk men mouse model mutant novel oncoprotein p21 polyposis pre-clinical programs rosiglitazone tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer is a major cause of cancer deaths in men and women in developed countries, and over a million new cases and 500,000 deaths occur each year. Inherited susceptibility to colorectal cancer only accounts for 15-25% of all cases, whereas, 75-85% of colon cancer is sporadic and associated with environmental/dietary factors. Studies in this laboratory have identified a series of 1,1-bis (3'-indolyl)-l- (p-substituted phenyl) methanes [C-substituted diindolylmethanes (DIMs)], which exhibit low in vivo toxicity but inhibit colon tumor and colon cancer cell growth through activation of peroxisome proliferator-activated receptor y (PPARy). We hypothesize that PPARy-active C-substituted DIMs represent a new class of mechanism-based drugs for treatment of colon cancer. Aim 1 will further investigate activation of PPAR ? -dependent transactivation and coactivator recruitment using a series of analogs containing both p-phenyl and indole ring substituents. These and other studies will be carried out in six colon cancer cell lines with defined molecular features including at least two cell lines which express wild-type PPARy (HT-29) and K422Q mutant PPARy, (HCT-15), which are non-responsive to other PPARy agonists such as rosiglitazone. The comparative growth inhibitory activities of rosiglitazone and PPARy-active C-substituted DIMs in colon cancer cell lines will be extensively investigated. Aim 2 will focus on the mechanisms of growth inhibition by PPARy-active C-substituted DIMs and based on preliminary studies, which appear to be associated with cell cycle genes/proteins (p21 and cyclin D1) and markers of differentiation such as caveolin 1 and 2. Initial studies will focus on the role of caveolin induction by PPARy-active C-substituted DIMs as a critical pathway for inhibition of cancer cell growth using wild-type and PPAR? -inactivated cells through RNA interference. Aim 3 will investigate inhibition of colon tumor growth in transgenic Min mice that are susceptible to colon cancer and athymic nude mouse models bearing colon cancer cells as xenografts and treated with PPARy-active C-substituted DIMs. The proposed studies will provide mechanistic insights on PPARy-dependent inhibition of colon cancer and identify compounds for future clinical studies.

描述（由申请人提供）：大肠癌是发达国家男性和女性癌症死亡的主要原因，每年发生超过一百万个新病例和500,000例死亡。对大肠癌的遗传敏感性仅占所有病例的15-25％，而75-85％的结肠癌是零星的，与环境/饮食因素有关。该实验室的研究鉴定了一系列1,1-双（3'-吲哚基）-L-（p-取代的苯基）甲烷[C-溶解的二烷基甲烷（DIMS）]，这些甲烷（DIMS）表现出较低的体内毒性，但抑制了结肠肿瘤和结肠癌细胞的生长，通过过氧化剂的活化蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白（propivativic）抑制了（per）。我们假设PPARY活性C取代的DIMS代表了一种基于机制的新药物，用于治疗结肠癌。 AIM 1将进一步研究PPAR的激活？ - 依赖性反式激活和共激活因子募集，使用一系列包含p-苯基和吲哚环取代基的类似物。这些研究和其他研究将在具有定义的分子特征的六个结肠癌细胞系中进行，其中包括至少两种表达野生型PPARY（HT-29）和K422Q突变体PPARY（HCT-15）的细胞系，它们对其他PPARY AMONISTS，例如Rosigiglitazone。在结肠癌细胞系中，罗格列酮和活性C-取代的DIM的比较生长抑制活性将得到广泛研究。 AIM 2将重点关注PPARY活性C-取代的DIM的生长抑制机制，并基于初步研究，这些研究似乎与细胞周期基因/蛋白质（P21和Cyclin d1 and Cyclin d1）和分化的标记以及Caveolin 1和2的分化标记有关，例如Caveolin 1和2。使用野生型和PPAR的癌细胞生长？通过RNA干扰激活细胞。 AIM 3将研究转基因最小小鼠中结肠肿瘤生长的抑制作用，这些小鼠容易受到结肠癌和伴有结肠癌细胞为异种移植的裸小鼠模型，并用Ppary-Active c cy依的DIM进行治疗。拟议的研究将提供有关PPARY依赖性抑制结肠癌的机理见解，并确定化合物以来的临床研究。