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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：
8650276
负责人：
SATISH K SRIVASTAVA
金额：
$ 30.22万
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 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8650276
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 Cancer cell line Carrier Proteins 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 Isoenzymes Kidney Lead Lesion Lipid Peroxidation Lipids Liver Lung MAP Kinase Gene Malignant Neoplasms Measures 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 Protein Kinase C Publishing Reactive Oxygen Species Regulation Role SW480 Sampling Signal Pathway Signal Transduction Small Interfering RNA Spleen Staging TP53 gene Testing Therapeutic Time Tissues Translating Transplantation Xenograft procedure angiogenesis base bench to bedside cancer cell cancer stem cell carcinogenesis chemokine colon carcinogenesis cytokine cytotoxic enzyme pathway fidarestat human DNA in vivo inflammatory marker inhibitor/antagonist innovation lymph nodes migration mortality mouse model novel oxaliplatin polyol prevent 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-?B-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）：我们最近证明醛糖还原酶（AR）是一种催化活性氧诱导的脂质过氧化衍生的脂质醛及其谷胱甘肽(GSH)-偶联物（GS-LDAs）还原的酶，是氧化应激诱导的致癌信号的重要介质。我们之前项目的结果表明，抑制AR通过抑制NF-?的表达来阻止人类结肠癌细胞的生长。b依赖性炎症标志物。我们还发现，抑制AR可阻止人结肠癌细胞在裸鼠异种移植物中的生长，以及在小鼠模型中偶氮甲烷诱导的异常隐窝灶的形成。此外，我们还发现抑制AR通过阻止癌细胞的侵袭、迁移和粘附以及血管生成来阻止结肠癌转移。虽然我们已经证明ar催化的GS-LDAs的还原产物，如GS-DHN，将致癌信号转导到下游的蛋白激酶C (PKC)，但调控细胞氧化还原稳态导致致癌的分子机制尚不清楚。我们假设脂质醛和gs偶联物介导了导致结肠癌生长和转移的抗癌和促癌信号级联反应。我们在这个项目中的目标是确定ar催化活性在其中起关键作用的机制