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Dietary histone deactylase inhibitors in prostate cancer prevention

膳食组蛋白脱乙酰酶抑制剂预防前列腺癌

基本信息

批准号：
7908175
负责人：
EMILY HO
金额：
$ 29.48万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7908175
关键词：
Accounting Acetylation Address Adverse effects American Animal Model Antineoplastic Agents Antioxidants Apoptosis Biological Availability Biological Markers Broccoli - dietary Cancer Etiology Cancer Patient Cell Cycle Arrest Cells Cessation of life Chemoprevention Chemopreventive Agent Chemoprotective Agent Clinical Clinical Trials Colorectal Consumption Cutaneous Development Diagnosis Diet Dietary Intervention Enzymes Epidemiologic Methods Epidemiologic Studies Epidemiologist Epigenetic Process Equilibrium Event Food Foundations Future Gene Expression Gene Expression Regulation Global Change Goals Health Health Care Costs Healthcare Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histone H3 Histone deacetylase inhibition Histones Histopathology Human Immunohistochemistry Incidence Inhibition of Apoptosis Injection of therapeutic agent Intake Intervention Intervention Studies Intervention Trial Investigation Isothiocyanates Link Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Metabolism Methods Modeling Modification Molecular Morbidity - disease rate Mus Normal Cell Nutritional Outcome Pathogenesis Pathologist Pathology Pathway interactions Patients Pattern Pharmaceutical Preparations Phase Play Population Population Sciences Populations at Risk Prevention strategy Prevention therapy Process Prostate Prostatic Neoplasms Public Health Qualifying Quality of life Recommendation Recurrence Reporting Repression Research Research Personnel Response Elements Risk Role Signal Pathway Signal Transduction Small Interfering RNA Sulforaphane Techniques Testing Time Tissues Training Tumor Suppression United States Up-Regulation Work base cancer cell cancer chemoprevention cancer prevention cancer risk cancer therapy cost cruciferous vegetable evidence base experience gene repression high risk high risk men histone acetyltransferase histone modification improved inhibitor/antagonist innovation insight interest lifestyle factors liquid chromatography mass spectrometry male men mortality mouse model novel novel strategies peripheral blood programs prostate cancer prevention prostate carcinogenesis protective effect translational study tumor tumor growth tumor progression urinary

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed non-cutaneous cancer, and is the second leading cause of cancer death in American men. The precise etiologic factors that initiate and enhance the progression of prostate cancer remains unknown, but epigenetic alterations and diet/lifestyle factors have come forth as significant contributing factors. During prostate cancer, alterations in acetylation patterns and increases in histone deacetylases are apparent. The use of pharmacological agents that inhibit HDACs for cancer prevention and therapy have gained significant interest. HDAC inhibitors cause increases in acetylated histones, selectively induce cell cycle arrest and apoptosis in cancer cells and have shown promise in cancer clinical trials. We have recently reported that sulforaphane (SFN), a compound found in cruciferous vegetables, suppresses tumor growth in animal models and inhibits HDAC activity in prostate. Based on these findings we formulated the following central hypothesis: Sulforaphane acts as an inhibitor of HDAC in the prostate, resulting in the induction of histone acetylation and de-repression of genes such as p21 and Bax, contributing to cell cycle arrest and apoptosis, and thus cancer prevention. The long term goal of these studies is to determine the mechanisms by which cruciferous vegetables act to decrease prostate cancer risk. The objective of these studies is to identify novel prostate chemoprotective agents that act via HDAC inhibition and de-repression of gene expression leading to cancer prevention. Specifically, we propose to 1) Characterize the effects of dietary SFN on development of prostate cancer in a mouse for prostate carcinogenesis. The working hypothesis is that SFN treatment will suppress prostate tumor development in TRAMP mice. Suppression of tumor development will be associated with inhibition of HDAC activity, increases in the levels of acetylated histones and enhancement of apoptosis. 2) Examine the requirement of HDAC inhibition for SFN induced apoptosis and chemoprevention. The working hypothesis is that HDAC inhibition by SFN is a key mechanism leading to SFN-induced p21 and Bax expression and apoptosis.3) Examine in humans the effects dietary consumption of cruciferous vegetables on SFN metabolism, HDAC activity and acetylated histone status. The working hypothesis is that high cruciferous vegetable intake will be associated with lower HDAC activity in peripheral blood and increase acetylated histone levels in prostate tissue of men at high risk for prostate cancer.

描述（申请人提供）：前列腺癌是最常诊断的非皮肤癌症，也是美国男性癌症死亡的第二大原因。启动和促进前列腺癌进展的确切病因因素仍不清楚，但表观遗传改变和饮食/生活方式因素已成为重要的促成因素。在前列腺癌期间，乙酰化模式的改变和组蛋白脱乙酰酶的增加是明显的。抑制HDAC的药理学试剂用于癌症预防和治疗的用途已经获得了显著的兴趣。HDAC抑制剂引起乙酰化组蛋白的增加，选择性地诱导癌细胞中的细胞周期停滞和凋亡，并且在癌症临床试验中显示出前景。我们最近报道了萝卜硫素（SFN），一种在十字花科蔬菜中发现的化合物，在动物模型中抑制肿瘤生长，并抑制前列腺中HDAC的活性。基于这些发现，我们提出了以下中心假设：萝卜硫素作为前列腺中HDAC的抑制剂，导致诱导组蛋白乙酰化和p21和Bax等基因的去抑制，有助于细胞周期阻滞和凋亡，从而预防癌症。这些研究的长期目标是确定十字花科蔬菜降低前列腺癌风险的机制。这些研究的目的是鉴定新型前列腺化学保护剂，其通过HDAC抑制和基因表达的去抑制而起作用，从而导致癌症预防。具体而言，我们提出1）表征饮食SFN对小鼠前列腺癌发展的影响，用于前列腺癌发生。工作假设是SFN治疗将抑制TRAMP小鼠中的前列腺肿瘤发展。肿瘤发展的抑制将与HDAC活性的抑制、乙酰化组蛋白水平的增加和细胞凋亡的增强相关。2)检查HDAC抑制对SFN诱导的细胞凋亡和化学预防的需要。工作假设是SFN对HDAC的抑制是导致SFN诱导的p21和Bax表达和凋亡的关键机制。3）在人类中检查十字花科蔬菜的饮食消耗对SFN代谢、HDAC活性和乙酰化组蛋白状态的影响。工作假设是，高十字花科蔬菜摄入量将与外周血中较低的HDAC活性相关，并增加前列腺癌高危男性前列腺组织中乙酰化组蛋白水平。