Targeting Egr-1 with Curcumin Analogs for Prostate Cancer Prevention

用姜黄素类似物靶向 Egr-1 预防前列腺癌

• 批准号: 7545393
• 负责人: MARCO BISOFFI
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545393
• 关键词: Address; Affect; Apoptosis; Appearance; Area; Benign; Biochemical Genetics; Biological Factors; Biological Markers; Biopsy; Cells; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Trials; Consumption; Curcumin; Databases; Development; Diagnostic Neoplasm Staging; Disease; Dose; Epidemiologic Studies; Epithelial; Event; Future; Gene Expression Microarray Analysis; Genes; Grapes; Green tea; Growth; Head and Neck Cancer; Histologic; Immunohistochemistry; Incidence; Intervention; Investigation; LNCaP; Lead; Life; Malignant Neoplasms; Malignant neoplasm of prostate; Molecular; Molecular Target; Normal tissue morphology; PC3 cell line; Phase; Phytochemical; Population; Premalignant; Prevention; Prevention strategy; Preventive; Preventive Intervention; Process; Prostate; Prostatic; Prostatic Neoplasms; Prostatic Tissue; Proteins; Public Health; Range; Rate; Reporter; Research Personnel; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Reduction; Sampling; Signal Transduction; Spices; Staging; Stromal Cells; Structure-Activity Relationship; Technology; Testing; Time; Tissues; Tomatoes; Transcriptional Activation; Tumeric; Tumor stage; United States; Up-Regulation; analog; base; cancer cell; cancer risk; concept; demographics; design; dietary supplements; disorder risk; drug discovery; gallocatechol; inhibitor/antagonist; lycopene; men; multidisciplinary; novel; paracrine; promoter; prostate cancer prevention; response; small molecule libraries; tool; transcription factor; trend; tumor; tumor initiation

DESCRIPTION (provided by applicant): Targeting Egr-1 with Curcumin Analogs for Prostate Cancer Prevention Bisoffi, Marco Project Summary The problem addressed in this proposal: Field cancerization, i.e. the presence of genetic and biochemical abnormalities in histologically normal tissues outside the tumor margins, may indicate a status of pre- malignancy in prostatic tissues that set the stage for tumor development. By definition, detectable molecular alterations in these tissues can represent early biomarkers of disease, even before disease is manifested histologically and long before a clinical problem arises. In addition, some of these changes, because of their early appearance, might be clinically useful targets for prevention, such as for example by dietary ingredients. While this concept has long been recognized for prominent compounds, such as from green tea (Epigallocatechin-3-gallate), tomatoes (Lycopene), grapes (Resveratrol), and Turmeric (Curcumin), the identification of the underlying mechanisms still awaits elucidation. Description of the investigation: We have identified an elevated expression of the transcription factor early growth response protein 1 (Egr-1) in tumor adjacent histologically normal prostatic tissues through gene array analysis, and confirmed our initial observation by reverse transcriptase polymerase chain reaction. We hypothesize that Egr-1 expression is not only indicative of prostatic field cancerization, but also represents a suitable target for defining new preventive strategies. We have assembled a multidisciplinary team of basic and clinical researchers to address the two following Specific Aims: Aim 1: Determine the expression of Egr-1 in pre-malignant, disease-free prostatic tissues. This will answer the question of whether Egr-1 expression is elevated in prostatic tissue at risk of tumor initiation. Aim 2: Identify lead compounds of Curcumin analogs inhibitory for Egr-1 expression. This will answer the question of whether Egr-1 expression can be regulated by natural dietary products. Importance of the investigation: Population based epidemiological studies indicate that dietary ingredients and natural products act as preventive agents such as Curcumin for prostate cancer. However, the underlying mechanisms are not known in most of the cases. A detailed understanding of these mechanisms is of utmost importance, as it will identify suitable targets and provide avenues towards the development of specific and directed prevention strategies. The present proposal contributes to the development of more effective strategies for prostate cancer prevention, thereby addressing the annual incidence rate of approximately 220,000 men in the United States alone. Targeting Egr-1 with Curcumin Analogs for Prostate Cancer Prevention Bisoffi, Marco Project Narrative The first phase of our project is designed to test the validity of a molecule termed Egr-1 that we found abnormally expressed in prostatic tissues adjacent to tumors. We hypothesize that abnormal Egr-1 expression indicates pre-malignancy and sets the stage for tumor development. In the second phase, we will identify analog compounds of the natural product Curcumin (found in Indian spices, such as Turmeric, Curry) that are capable of inhibiting Egr-1 expression. We expect that such novel and potent compounds will ultimately lead to clinical trials for prostate cancer prevention using dietary supplements.

描述（由申请人提供）：用姜黄素类似物靶向 Egr-1 预防前列腺癌 Bisoffi, Marco 项目摘要 本提案中解决的问题：局部癌化，即肿瘤边缘外的组织学正常组织中存在遗传和生化异常，可能表明前列腺组织的癌前状态，为肿瘤的发展奠定了基础。根据定义，这些组织中可检测到的分子改变可以代表疾病的早期生物标志物，甚至在疾病在组织学上表现出来之前以及在临床问题出现很久之前。此外，其中一些变化由于其早期出现，可能是临床上有用的预防目标，例如通过饮食成分。虽然这一概念早已在绿茶（表没食子儿茶素-3-没食子酸酯）、西红柿（番茄红素）、葡萄（白藜芦醇）和姜黄（姜黄素）等重要化合物中得到认可，但其潜在机制的识别仍有待阐明。研究描述：通过基因阵列分析，我们发现转录因子早期生长反应蛋白 1 (Egr-1) 在肿瘤邻近的组织学正常前列腺组织中表达升高，并通过逆转录酶聚合酶链反应证实了我们的初步观察结果。我们假设 Egr-1 表达不仅表明前列腺癌化，而且代表了定义新预防策略的合适目标。我们组建了一个由基础和临床研究人员组成的多学科团队，以解决以下两个具体目标： 目标 1：确定 Egr-1 在癌前、无病前列腺组织中的表达。这将回答以下问题：前列腺组织中 Egr-1 表达是否在肿瘤发生风险中升高。目标 2：鉴定姜黄素类似物抑制 Egr-1 表达的先导化合物。这将回答Egr-1表达是否可以通过天然膳食产品调节的问题。调查的重要性：基于人群的流行病学研究表明，膳食成分和天然产品可以作为前列腺癌的预防剂，例如姜黄素。然而，在大多数情况下，根本机制尚不清楚。详细了解这些机制至关重要，因为它将确定合适的目标并为制定具体和有针对性的预防战略提供途径。本提案有助于制定更有效的前列腺癌预防策略，从而解决仅美国约 220,000 名男性的年发病率问题。用姜黄素类似物靶向 Egr-1 预防前列腺癌 Bisoffi，Marco 项目叙述 我们项目的第一阶段旨在测试一种名为 Egr-1 的分子的有效性，我们发现该分子在肿瘤附近的前列腺组织中异常表达。我们假设异常的 Egr-1 表达表明癌前病变并为肿瘤的发展奠定了基础。在第二阶段，我们将鉴定能够抑制 Egr-1 表达的天然产物姜黄素（在印度香料中发现，如姜黄、咖喱）的类似化合物。我们预计这种新颖且有效的化合物最终将导致使用膳食补充剂预防前列腺癌的临床试验。