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：
7777848
负责人：
EMILY HO
金额：
$ 22.78万
依托单位：
OREGON STATE UNIVERSITY
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：
2007-05-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7777848
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（由申请人提供）：前列腺癌是最常诊断的非皮肤癌，也是美国男性癌症死亡的第二大原因。引发和促进前列腺癌进展的确切病因尚不清楚，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。使用抑制 HDAC 的药物来预防和治疗癌症已引起人们的极大兴趣。 HDAC 抑制剂会导致乙酰化组蛋白增加，选择性诱导癌细胞的细胞周期停滞和细胞凋亡，并在癌症临床试验中显示出前景。我们最近报道，萝卜硫素 (SFN) 是一种在十字花科蔬菜中发现的化合物，可抑制动物模型中的肿瘤生长并抑制前列腺中的 HDAC 活性。基于这些发现，我们制定了以下中心假设：萝卜硫素作为前列腺中 HDAC 的抑制剂，导致组蛋白乙酰化的诱导和 p21 和 Bax 等基因的去抑制，从而导致细胞周期停滞和细胞凋亡，以及从而预防癌症。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。这些研究的目的是确定新型前列腺化学保护剂，通过 HDAC 抑制和基因表达去抑制发挥作用，从而预防癌症。具体来说，我们建议 1) 表征膳食 SFN 对小鼠前列腺癌发展的影响，以了解前列腺癌的发生。目前的假设是，SFN 治疗将抑制 TRAMP 小鼠前列腺肿瘤的发展。肿瘤发展的抑制与 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有关。 2) 检查 HDAC 抑制对 SFN 诱导的细胞凋亡和化学预防的要求。目前的假设是，SFN 抑制 HDAC 是导致 SFN 诱导的 p21 和 Bax 表达和细胞凋亡的关键机制。3) 研究人类饮食中食用十字花科蔬菜对 SFN 代谢、HDAC 活性和乙酰化组蛋白状态的影响。目前的假设是，高十字花科蔬菜摄入量与前列腺癌高危男性外周血中 HDAC 活性降低有关，并增加前列腺组织中乙酰化组蛋白水平。