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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：
9246437
负责人：
KOTA VENKATA RAMANA
金额：
$ 31.2万
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 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9246437
关键词：
4 hydroxynonenal Abbreviations Aberrant crypt foci Ablation Adhesions Aldehyde Reductase Aldehydes Antineoplastic Agents Apoptosis Apoptotic Azoxymethane Beds Biopsy Biopsy Specimen Cancer Cell Growth Cause of Death Cell Death Cell model Cell surface Cessation of life Cetuximab Chemoprevention Chemopreventive Agent Clinical Protocols Clinical Trials Colon Carcinoma Colorectal Cancer Cyclophosphamide Cytotoxic agent Development Diabetic Neuropathies Dinoprostone Drug Transport Enzymes Fluorouracil Foundations Functional disorder Funding Glutathione Goals Growth Growth Factor HCT116 Cells HT29 Cells Homeostasis Human Implant In Situ Hybridization In Vitro Inflammatory Injectable Isoenzymes Kidney Lead Lesion Lipid Peroxidation Lipid Peroxides Lipids Liver Lung MAP Kinase Gene Malignant Neoplasms Mediating Mediator of activation protein Metastatic Neoplasm to the Liver Microscopic Modeling Molecular Mus NF-kappa B Neoplasm Metastasis Nude Mice Operative Surgical Procedures Oxidation-Reduction Oxidative Stress Participant Pathology Pathway interactions Pharmaceutical Preparations Phase III Clinical Trials Play Predisposition Preventive measure Protein Kinase C Publishing Reactive Oxygen Species Regulation Role SW480 Sampling Signal Pathway Signal Transduction Small Interfering RNA Spleen TP53 gene Testing Therapeutic Time Tissues Translating Transplantation Xenograft procedure angiogenesis base bench to bedside cancer cell cancer stem cell carcinogenesis carcinogenicity chemokine colon cancer cell line colon carcinogenesis cytokine cytotoxic enzyme pathway fidarestat histopathological examination human DNA in vivo inflammatory marker inhibitor/antagonist innovation lymph nodes migration mortality mouse model novel novel drug class novel therapeutics oxaliplatin polyol prevent protein transport public health relevance translational study tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): We have recently demonstrated that aldose reductase (AR), an enzyme that catalyzes the reduction of reactive oxygen species-induced lipid peroxidation-derived lipid aldehydes and their glutathione (GSH)- conjugates (GS-LDAs), is an essential mediator of oxidative stress-induced carcinogenic signals. Our results from the previous project period have shown that inhibition of AR prevents the growth of human colon cancer cells by inhibiting the expression of NF-κB-dependent inflammatory markers. We have also shown that inhibition of AR prevents growth of human colon cancer cells in nude mouse xenografts, as well as azoxymethane-induced aberrant crypt foci formation in a mouse model. Further, we have also shown that inhibition of AR prevents colon cancer metastasis by preventing cancer cell invasion, migration and adhesion, as well as angiogenesis. Although we have shown that AR-catalyzed reduced products of GS-LDAs, such as GS-DHN, transduce carcinogenic signals downstream to protein kinase C (PKC), the molecular mechanisms that regulate cellular redox homeostasis leading to carcinogenesis are not clearly understood. We hypothesize that lipid aldehydes and GS-conjugates mediate anti-carcinogenic and pro-carcinogenic signaling cascades that lead to colon cancer growth and metastasis. Our goal in this project is to determine the mechanisms by which AR-catalytic activity plays a critical role in the regulation of colon carcinogenesis using human colon cancer cells, isolated human colon cancer stem cells in vitro, as well as in vivo orthotopic mouse models. Our long-term goal is to develop inhibitors of AR as safe and effective preventive measures for colorectal cancer growth and metastasis. Our specific aims are to: 1) determine how glutathione-lipid aldehydes (GS-LDAs) regulate NF-kB and Nrf-2 pathways that mediate CRC cell growth/death; 2) elucidate how AR inhibition prevents growth and metastasis of human CRC biopsy samples and colon cancer stem cells implanted in athymic nude mice; and 3) determine how AR inhibition prevents the survival of colon cancer stem cells. Completion of this project will elucidate the molecular mechanisms by which AR regulates cellular redox homeostasis, carcinogenesis and tumor growth and metastasis, and lay the foundation for the use of AR inhibitors as novel chemopreventive drugs for colorectal cancer.

描述（由申请人提供）：我们最近证明了醛糖还原酶（AR）是一种催化活性氧诱导的脂质过氧化物衍生的脂质醛及其谷胱甘肽（GSH）-缀合物（GS-LDA）还原的酶，是氧化应激诱导的致癌信号的重要介质。我们在前一个项目期间的结果表明，抑制AR通过抑制以下蛋白的表达来阻止人结肠癌细胞的生长： NF-κ B依赖性炎症标志物。我们还表明，AR的抑制可以防止裸鼠异种移植物中人结肠癌细胞的生长，以及在小鼠模型中氧化偶氮甲烷诱导的异常隐窝灶形成。此外，我们还表明，AR的抑制通过防止癌细胞侵袭、迁移和粘附以及血管生成来防止结肠癌转移。虽然我们已经表明，AR催化的还原产物的GS-LDAs，如GS-DHN，致癌信号下游的蛋白激酶C（PKC），调节细胞氧化还原稳态导致致癌的分子机制还没有清楚地了解。我们假设脂质醛和GS-缀合物介导导致结肠癌生长和转移的抗癌和促癌信号级联。我们在这个项目中的目标是确定AR催化活性在以下方面发挥关键作用的机制：使用人结肠癌细胞、体外分离的人结肠癌干细胞以及体内原位小鼠模型调节结肠癌发生。我们的长期目标是开发AR抑制剂作为结直肠癌生长和转移的安全有效的预防措施。我们的具体目标是：1）确定谷胱甘肽-脂质醛（GS-LDA）如何调节介导CRC细胞生长/死亡的NF-kB和Nrf-2途径; 2）阐明AR抑制如何防止植入无胸腺裸鼠中的人CRC活检样品和结肠癌干细胞的生长和转移;和3）确定AR抑制如何防止结肠癌干细胞的存活。本项目的完成将阐明AR调节细胞氧化还原稳态、致癌作用以及肿瘤生长和转移的分子机制，并为AR抑制剂作为新型结直肠癌化学预防药物的应用奠定基础。