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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：
7996629
负责人：
SATISH K SRIVASTAVA
金额：
$ 30.39万
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/7996629
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 HT29 Cells 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 Platelet-Derived Growth Factor Positioning Attribute Production Property Protein Dephosphorylation RNA Interference Reactive Oxygen Species Regulation Research Risk Risk Factors Role Signal Pathway Signal Transduction Skin Spleen Staging Stimulus TNF gene Testing Therapeutic Therapeutic Uses Tissues Transcription Factor AP-1 Work Xenograft procedure activating transcription factor base cancer cell carcinogenesis cellular targeting colon cancer cell line colon carcinogenesis cytokine experience in vivo inflammatory marker inhibitor/antagonist innovation macrophage neoplastic cell novel prevent 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.

描述（申请人提供）：慢性炎症性疾病和氧化应激是结直肠癌（CRC）的主要危险因素，结直肠癌是癌症患者的第二大死因。然而，氧化应激和炎症标志物增加导致结直肠癌的机制尚不清楚。了解这些生化机制，特别是活性氧 (ROS) 增加在 CRC 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，醛糖还原酶 (AR) 是一种催化 ROS 诱导的脂醛及其谷胱甘肽缀合物（例如 HNE 和 GS-HNE 还原为 DHN 和 GS-DHN）的酶，是人结肠癌细胞中生长因子和细胞因子诱导的 NF-:B 激活的必需介质。此外，我们还表明，SiRNA 抑制 AR 或消除 AR 可以阻止培养物以及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 (ARI) 用于化学预防 CRC。我们现在将系统地检验我们的假设，即ROS的作用部分是由AR催化的还原性脂质过氧化衍生醛（LDA）及其代谢物介导的，通过研究AR在介导培养细胞、裸鼠异种移植物和CRC小鼠模型中生长因子诱导的癌症生长中的作用。我们的具体目标是 1) 研究 AR 抑制对生长因子诱导的培养人结肠癌细胞生长进展的影响，2) 描述 AR 抑制/消融对裸鼠异种移植物中结肠癌进展的影响，以及 3) 描述 AR 抑制在小鼠模型中化学和遗传诱导的 CRC 中的化学预防功效。这些研究的完成应能确定 AR 减少的 LDA 在介导致癌信号中的分子机制，并导致使用 AR 抑制剂作为 CRC 的优秀化学预防药物。