Chemoprevention of Colorectal Cancer by Aldose Reductase Inhibition

通过抑制醛糖还原酶化学预防结直肠癌

基本信息

批准号：
7738905
负责人：
SATISH K SRIVASTAVA
金额：
$ 31.33万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7738905
关键词：
Ablation Address Adenocarcinoma Cell Affect Aldehyde Reductase Aldehydes Antioxidants Azoxymethane Biochemical Cancer Cell Growth Cancer Patient Cause of Death Cell Proliferation Cell physiology Cells Cessation of life Chemoprevention Chemopreventive Agent Chronic Clinical Protocols Clinical Trials Colon Carcinoma Colorectal Cancer Colorectal Neoplasms Cultured Cells Data Development Diagnosis Dinoprostone Disease Dose Endotoxins Enzymes Epidemiologic Studies Event Fibroblast Growth Factor Foundations Functional disorder Future Generations Genes Glutathione Goals Growth Growth Factor Homeostasis Human Implant Inflammation Inflammatory Inflammatory Response Injury Knockout Mice Lead Light Lipid Peroxidation Lipids Liver Malignant Neoplasms Measures Mediating Mediator of activation protein Metabolic Metabolism Methods Modeling Molecular Molecular Target Mus Normal tissue morphology Nude Mice Oxidants Oxidation-Reduction Oxidative Stress Participant Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Positioning Attribute Principal Investigator Production Property Protein Dephosphorylation RNA Interference Reactive Oxygen Species Regulation Research Risk Risk Factors Role Signal Pathway Signal Transduction Skin Spleen Staging Stimulus Testing Therapeutic Therapeutic Uses Tissues Transcription Factor AP-1 Work Xenograft procedure activating transcription factor base cancer cell carcinogenesis colon cancer cell line colon carcinogenesis cytokine experience in vivo inflammatory marker inhibitor/antagonist innovation macrophage neoplastic cell novel prevent programs sorbinil tolrestat transcription factor tumor tumor growth tumor progression tumorigenesis tumorigenic upstream kinase

项目摘要

DESCRIPTION (provided by applicant): Chronic inflammatory diseases and oxidative stress are major risk factors of colorectal cancer (CRC), the second-ranked cause of death among cancer patients. However, the mechanisms through which increased oxidative stress and inflammatory markers cause CRC are not well understood. Understanding these biochemical mechanisms, especially the role of increased reactive oxygen species (ROS) in the pathophysiology of CRC, will help in developing better therapeutic strategies. We have recently demonstrated that aldose reductase (AR) an enzyme that we have shown catalyzes the reduction of ROS-induced lipid aldehydes and their glutathione-conjugates (such as HNE and GS-HNE to DHN and GS-DHN),is an obligatory mediator of growth factor and cytokine-induced NF-:B activation in human colon cancer cells. Further, we have shown that AR inhibition or ablation by SiRNA prevents the growth of colon cancer cells in culture as well as in nude mice xenografts. Our long term goal is to understand the mechanisms by which AR contributes to CRC progression, and to develop AR inhibitors (ARIs) for chemoprevention of CRC. We will now systematically examine our hypothesis that the effects of ROS are in part mediated by AR- catalyzed reduced lipid peroxidation-derived aldehydes (LDAs) and their metabolites by investigating the role of AR in mediating growth factor-induced cancer growth in cultured cells, nude mice xenografts and murine models of CRC. Our specific aims are 1) Investigate the effects of AR inhibition on the growth factor-induced progression of cultured human colon cancer cell growth, 2) Delineate the effects of AR inhibition/ablation on colon cancer progression in nude mouse xenografts, and 3) Delineate the chemopreventive efficacy of AR inhibition in chemically and genetically-induced CRC in murine models. Completion of these studies should identify the molecular mechanisms of AR- reduced LDAs in mediating carcinogenic signals, and lead to use of AR inhibitors as excellent chemopreventive drugs for CRC.HEALTH Relevance: colon cancer is the second leading cause of death among the cancer patients in US. Our project will determine the mechanisms of colon carcinogenesis, and ultimately lead to the development of new chemopreventive approaches to prevent death from colon cancer.

描述（由申请人提供）：慢性炎症性疾病和氧化应激是大肠癌（CRC）的主要危险因素，这是癌症患者的第二级死亡原因。但是，氧化应激增加和炎症标志物引起CRC的机制尚不清楚。了解这些生化机制，尤其是活性氧（ROS）在CRC的病理生理学中的作用，将有助于制定更好的治疗策略。我们最近证明，我们已经表明催化ROS诱导的脂质醛及其谷胱甘肽 - 偶联物（例如HNE和GS-HNE to DHN和GS-DHN）的促催化酶是一种强制性介导，是生长因子的强制性介导和细胞质诱导的Nf激活癌症。此外，我们已经表明，siRNA的AR抑制或消融可防止培养物和裸鼠异种移植物中结肠癌细胞的生长。我们的长期目标是了解AR促进CRC进展的机制，并开发AR抑制剂（ARIS）进行CRC化学预防。现在，我们将系统地研究我们的假设，即ROS的作用部分是由AR催化的降低脂质过氧化过氧化的醛（LDAS）及其代谢产物介导的，通过研究AR在介导生长因子诱导的癌症生长中培养的细胞中的作用，裸小鼠Xenografts和murcc的CRC的癌症生长中的作用。 Our specific aims are 1) Investigate the effects of AR inhibition on the growth factor-induced progression of cultured human colon cancer cell growth, 2) Delineate the effects of AR inhibition/ablation on colon cancer progression in nude mouse xenografts, and 3) Delineate the chemopreventive efficacy of AR inhibition in chemically and genetically-induced CRC in murine models.这些研究的完成应确定在介导致癌信号中降低ARS的LDA的分子机制，并导致AR抑制剂作为CRC的优秀化学预防药物。健康相关性：结肠癌是美国癌症患者中的第二大主要死亡原因。我们的项目将确定结肠癌发生的机制，并最终导致开发新的化学预防方法，以防止结肠癌死亡。