Colon Cancer Chemoprevention and COX-2 Suppression by Ursodeoxycholic Acid

熊去氧胆酸的结肠癌化学预防和 COX-2 抑制

• 批准号: 8141038
• 负责人: SHARAD KHARE
• 金额: --
• 依托单位: EDWARD HINES JR VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8141038
• 关键词: Aberrant crypt foci; Adverse effects; Affect; Age; Apoptosis; Attention; Azoxymethane; Bile Acids; C-terminal; Cancer Cell Growth; Cancer Etiology; Cancer Patient; Cardiovascular system; Cell Culture Techniques; Cell Cycle Arrest; Cell Death; Cell Survival; Cells; Chemopreventive Agent; Cholic Acids; Clinical; Colon Carcinoma; Colonic Adenoma; Colonic Neoplasms; Colorectal Adenoma; Coupled; Data; Development; Diagnosis; Diet; Dysplasia; Ensure; Epithelial Cells; Foundations; Gastroenterology; Gene Expression; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Healthcare; Healthcare Systems; Human; In Vitro; Individual; Investigation; Lasers; Lesion; Liver diseases; Malignant Neoplasms; Modeling; Molecular; Mutagens; Nude Mice; PTGS2 gene; Patients; Phase; Premalignant; Preventive; Primary biliary cirrhosis; Protein Fragment; Proteins; Rattus; Recurrence; Regulation; Research; Risk; Rodent; Role; Sampling; Screening procedure; Stromal Cells; Testing; Therapeutic; Therapeutic Intervention; Time; Treatment Cost; Treatment Efficacy; Tumor Promotion; Ulcerative Colitis; United States; Ursodeoxycholic Acid; Veterans; activated Protein C; adenoma; cancer cell; cancer chemoprevention; cancer prevention; carcinogenesis; double-blind placebo controlled trial; evidence base; high risk; human disease; improved; in vivo; inhibitor/antagonist; insight; mortality; novel; prevent; primary sclerosing cholangitis; protein expression; tumor; tumor progression; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): Recent progress in Cox-2 selective inhibitors have shown promise to prevent colon cancer, but untoward cardiovascular side effects have dampened the enthusiasm for these agents. Since selective Cox-2 inhibitors appear problematic, increasing efforts are being made to identify other effective and safer chemopreventive agents. A large, phase III, double blind, placebo-controlled trial of Ursodeoxycholic acid (UDCA) to prevent the recurrence of colorectal adenoma was associated with a statistically significant reduction in recurrence of adenomas with high-grade dysplasia. My long-term research objectives are to elucidate the mechanisms by which UDCA exerts anticarcinogenic effects with respect to colon cancer. We have previously demonstrated that supplemental dietary cholic acid promoted the development of azoxymethane-induced rat colonic tumors. In contrast, dietary UDCA inhibited tumorigenesis and suppressed cholic acid-induced tumor promotion. To examine the mechanisms by which UDCA causes anticarcinogenic effects, studies in the proposal demonstrated that UDCA inhibited wild-type Ras activated tumors and generated RasGTPase activating protein (RasGAP) -N and -C terminal fragments. RasGAP C-terminal fragment sensitizes colon cancer cells towards UDCA-induced cell cycle arrest and suppresses Cox-2 expression in these cells. One of the major goals of this investigation is to provide proof of principle that RasGAP C-fragment protein will be useful in improving the efficacy of UDCA in colon cancer prevention. This will be achieved by investigating the growth of tumor xenografts in nude mice established with RasGAP C-transfectants and the effect of UDCA on regulators of G0/G1 cell cycle arrest in cell culture. Additionally, we will also investigate the effect of Intratumoral delivery of a permeable RasGAP C-fragment protein on tumor xenografts. Another goal of this investigation is to identify and characterize the transcriptional and post-transcriptional mechanisms by which RasGAP C-terminal fragment alters constitutive Cox-2 gene expression in colon cancer cells and UDCA suppresses Cox-2 in Aberrant Crypt Foci (ACF), the putative premalignant precursors of colon cancer. This will be achieved by investigating the stromal and epithelial cells of laser capture microdissected ACF in azoxymethane model of colonic carcinogenesis. We will extend our investigation to human samples by isolating ACFs from patients and study RasGAP fragments and Cox-2 regulators to ensure that regulatory components identified in vitro and in vivo are relevant to human disease. Studies in this proposal are, therefore, important for gaining insights into basic molecular regulation of Cox-2 by RasGAP C-fragments, a novel and unexplored mechanism. It will be useful in the development of better therapeutic interventions, as potential Cox-2 inhibitors are considered toxic for human use. PUBLIC HEALTH RELEVANCE: Significance and Relevance to Veterans Health Care The VA health care system has emphasized the importance of colon cancer screening, diagnosis and treatment. In 2002 the VA Gastroenterology Field Advisory Group estimated that there were 4.7 million veterans over the age of 50 and thus at risk for colon cancer and in need of screening. The 2006 VA directive on colon cancer screening noted that colon cancer screening coupled with the cost of treatment for colon cancer makes the issue of cancer prevention in the VA a high priority. The proposed research has great potential to eventually affect the clinical approach to colon cancer by elucidating the mechanisms of a truly preventive approach to colon cancer.

描述(由申请人提供)： COX-2选择性抑制剂的最新进展显示出预防结肠癌的希望，但不良的心血管副作用抑制了人们对这些药物的热情。由于选择性COX-2抑制剂似乎存在问题，人们正在加紧努力寻找其他有效和更安全的化学预防药物。一项关于熊去氧胆酸(UDCA)预防结直肠腺瘤复发的大型、III期、双盲、安慰剂对照试验与腺瘤高度不典型增生的复发率在统计学上显著降低有关。我的长期研究目标是阐明UDCA在结肠癌方面发挥抗癌作用的机制。我们先前已经证明，补充膳食胆酸促进了偶氮甲烷诱导的大鼠结肠肿瘤的发展。相比之下，饮食中的UDCA抑制了肿瘤的形成，并抑制了胆酸诱导的肿瘤促进作用。为了研究UDCA产生抗癌作用的机制，该提案中的研究表明，UDCA抑制野生型RAS激活的肿瘤，并产生RasGTPase激活蛋白(RasGAP)-N和-C末端片段。RasGAP C末端片段使结肠癌细胞对UDCA诱导的细胞周期停滞敏感，并抑制COX-2在这些细胞中的表达。这项研究的主要目的之一是提供RasGAP C-片段蛋白将在提高UDCA预防结肠癌的有效性方面有用的原理证据。这将通过研究RasGAP C-转基因裸鼠移植瘤的生长以及UDCA在细胞培养中对G0/G1期细胞周期停滞的调节作用来实现。此外，我们还将研究瘤内注射可渗透的RasGAP C-片段蛋白对肿瘤移植瘤的影响。本研究的另一个目的是确定和表征RasGAP C末端片段改变结肠癌细胞COX-2结构性表达以及UDCA在异常隐窝Foci(ACF)中抑制COX-2表达的转录和转录后机制。ACF是结肠癌的癌前病变。这将通过研究激光捕获显微切割的ACF的间质和上皮细胞在偶氮甲烷结肠癌变模型中实现。我们将通过从患者中分离ACF将我们的研究扩展到人类样本，并研究RasGAP片段和COX-2调节器，以确保在体外和体内发现的调节成分与人类疾病相关。因此，这项研究对于深入了解RasGAP C-片段对COX-2的基本分子调控是重要的，RasGAP C-片段是一种新的和未知的机制。这将有助于开发更好的治疗干预措施，因为潜在的COX-2抑制剂被认为对人类使用是有毒的。 公共卫生相关性： 退伍军人保健的重要性和相关性退伍军人保健系统强调了结肠癌筛查、诊断和治疗的重要性。2002年，退伍军人管理局胃肠病实地咨询组估计，50岁以上的退伍军人中有470万人有患结肠癌的风险，需要进行筛查。2006年退伍军人事务部关于结肠癌筛查的指令指出，结肠癌筛查加上结肠癌的治疗费用，使退伍军人事务部的癌症预防问题成为高度优先的问题。这项拟议的研究具有巨大的潜力，通过阐明真正预防结肠癌的方法的机制，最终影响结肠癌的临床治疗方法。