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.

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.我们从上一个项目期间开始的结果表明，AR的抑制通过抑制NF-依赖性炎症标记的表达来阻止人类结肠癌细胞的生长。我们还表明，对AR的抑制可防止裸小鼠异种移植物中人类结肠癌细胞的生长，以及在小鼠模型中偶氮甲烷诱导的异常隐窝灶形成。此外，我们还表明，对AR的抑制可通过预防癌细胞侵袭，迁移和粘附以及血管生成来防止结肠癌转移。尽管我们已经表明，AR催化的GS-LDAS的降低产物，例如GS-DHN，转导致癌信号，向下游到蛋白激酶C（PKC），这是调节导致癌变发生的细胞氧化还原稳态的分子机制。我们假设脂质醛和GS偶联物介导导致结肠癌生长和转移的抗癌和促癌信号传导级联。我们在该项目中的目标是确定AR催化活动在使用人类结肠癌细胞，分离的人类结肠癌干细胞以及体内原位小鼠模型来调节结肠癌发生。我们的长期目标是开发AR的抑制剂作为结直肠癌生长和转移的安全有效预防措施。我们的具体目的是：1）确定谷胱甘肽脂醛醛（GS-LIDAS）如何调节NF-KB和NRF-2途径，以介导CRC细胞生长/死亡； 2）阐明AR抑制如何防止植入无胸腺裸鼠的人CRC活检样品和结肠癌干细胞的生长和转移； 3）确定AR抑制如何防止结肠癌干细胞的存活。该项目的完成将阐明AR调节细胞氧化还原稳态，癌变和肿瘤生长和转移的分子机制，并为将AR抑制剂用作新型化学预防性药物奠定了基础。