Equol and Regulation of Prostate Growth

雌马酚与前列腺生长的调节

基本信息

批准号：
7471957
负责人：
Robert J Handa
金额：
$ 32.74万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7471957
关键词：
Address Adenosylmethionine Decarboxylase Adult Affinity Age Agonist Anabolism Androgen Analogues Androgen Antagonists Androgen Receptor Androgens Animal Feed Animal Model Animals Asians Benign Benign Prostatic Hypertrophy Binding Biological Assay Cell Cycle Cell Line Cells Cessation of life Chemopreventive Agent Complex Development Diet Disease Dose Early Diagnosis Elderly Enzymes Estrogen Antagonists Estrogen Receptor beta Estrogen Receptors Estrogens Event Exposure to Gene Expression Genes Genistein Goals Growth Hormones Human Image Imaging Techniques In Vitro Incidence Injection of therapeutic agent Intestines Isoflavones LNCaP Lobe Luciferases Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of prostate Mediating Metabolism Modeling Molecular Monitor Mus Neoplasm Metastasis PC3 cell line Pathology Pathway interactions Photons Phytoestrogens Polyamines Population Property Prostate Prostate carcinoma Prostatic Neoplasms Prostatic hypertrophy Public Health Rattus Receptor Activation Regulation Reporter Genes Reverse Transcriptase Polymerase Chain Reaction Risk Factors Rodent Rodent Model Role Spermidine Spermine Stanolone Symptoms Testing Testosterone Testosterone 5-alpha-Reductase Thinking Time Tissues Transfection Transgenic Mice United States Viral Week base cancer diagnosis cell growth cholestenone 5 alpha-reductase daidzein dietary supplements equol feeding in vivo interest knock-down lymph nodes male men mouse model neoplastic cell novel prevent response selective expression size small hairpin RNA tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): This project will define the mechanism by which equol, an isoflavone metabolite, acts to inhibit normal and pathological growth of the prostate gland. In the United States, prostate cancer is the most frequently diagnosed cancer in men, and ranks second among cancer-related male deaths. The development of prostate cancer involves a complex interplay of numerous factors, however lifetime exposure to androgens, and advancing age, are two necessary etiological factors. Similarly, the development of benign prostatic hypertrophy (BPH) is also dependent upon androgen exposure and it is estimated that over half of the male population in the United States over the age of 60 have symptoms of BPH. The importance of androgen in prostate gland pathology is evidenced by current therapies for these diseases, which include reduction in circulating testosterone; inhibition of 5-alpha reductase, an enzyme that synthesizes the potent androgen, dihydrotestosterone; or blocking the actions of the androgen receptor. Diet is an important consideration when examining risk factors for hormone-dependent diseases such as prostate cancer. Asian men, on an eastern diet, have the lowest incidence of prostate cancer in the world. The basis for this correlation may be the presence of estrogen-like isoflavones (genistein and daidzein), in their diet. We have recently shown that equol, a product of isoflavone metabolism, has anti- androgenic properties as well. Equol selectively binds dihydrotestostserone and prevents androgen receptor activation to reduce androgen-dependent prostate growth. Equol is the principal metabolite of daidzein. It circulates at high levels, and is concentrated in the prostate. Moreover, equol can selectively bind estrogen receptor beta to activate an anti-proliferative cascade in prostate. Thus, equol possesses a unique dual action to inhibit prostate growth by 1) preventing proliferative actions of androgens, and 2) activating anti-proliferative actions of ERbeta. However, only about 30% of all humans have the correct intestinal flora to produce equol. In these studies, we will test the hypothesis that pathological growth of the prostate gland can be prevented or delayed by dietary equol. We will also determine the cellular mechanisms whereby equol provides such protection. These studies utilize the TRAMP mouse line where spontaneous prostate tumors develop in adult males making this particularly useful for studying the chemopreventive actions of equol. In addition, we will utilize an orthotopic injection model whereby human prostate carcinoma lines that express a luciferase reporter gene are injected into host mice and monitored by in vivo imaging techniques to determine the effects of equol, on growth of prostate tumors. Lastly, we will determine if equol can act by altering the polyamine biosynthetic pathway, thereby inhibiting cell cycle and tumor growth. PUBLIC HEALTH RELEVANCE: Prostate cancer is the most frequently diagnosed cancer in men, and ranks second among cancer-related male deaths in the United States. In this application, we will test the hypothesis that pathological growth of the prostate gland can be prevented or delayed by dietary administration of equol, a product of isoflavone metabolism that has anti-androgenic and estrogen receptor beta activating properties. The long-term goal of this project is to define the mechanism by which equol acts to inhibit the pathological growth of the prostate gland

描述（由申请人提供）：该项目将定义equol（异黄酮代谢产物）起作用的机制，可抑制前列腺腺的正常和病理生长。在美国，前列腺癌是男性最常见的癌症，在与癌症相关的男性死亡中排名第二。前列腺癌的发展涉及许多因素的复杂相互作用，但是终生暴露于雄激素和年龄是两个必要的病因因素。同样，良性前列腺肥大（BPH）的发展也取决于雄激素的暴露，据估计，在美国60岁以上的美国，超过一半的男性人口具有BPH的症状。当前对这些疾病的疗法证明了雄激素在前列腺病理学中的重要性，包括减少循环睾丸激素。抑制5-α还原酶，一种酶，可合成有效的雄激素二氢睾丸激素；或阻止雄激素受体的作用。饮食是研究激素依赖性疾病（例如前列腺癌）的危险因素时的重要考虑因素。亚洲男性在东部饮食中的前列腺癌发病率最低。这种相关性的基础可能是饮食中存在类似雌激素的异黄酮（染料蛋白酶和大达兹蛋白酶）的存在。我们最近表明，异黄酮代谢的产物Equol具有抗雄激素特性。均值选择性地结合二氢固醇，并防止雄激素受体激活以减少依赖雄激素的前列腺生长。 Equol是Daidzein的主要代谢产物。它以高水平循环，并集中在前列腺中。此外，Equol可以选择性地结合雌激素受体β以激活前列腺中的抗增殖性级联反应。因此，Equol具有独特的双重作用来抑制前列腺生长1）防止雄激素的增殖作用，以及2）激活Erbeta的抗增殖作用。但是，只有大约30％的所有人具有正确的肠菌群来产生雌激素。在这些研究中，我们将检验以下假设：饮食中的雌性可以预防或延迟前列腺的病理生长。我们还将确定Equol提供此类保护的细胞机制。这些研究利用了流浪小鼠系列，在成年雄性中出现自发前列腺肿瘤，使得这对于研究雌激素的化学预防作用特别有用。此外，我们还将利用一种原位注射模型，通过该模型将表达荧光素酶报告基因的人类前列腺癌系注入宿主小鼠，并通过体内成像技术监测，以确定equol的影响，对前列腺肿瘤的生长。最后，我们将确定Equol是否可以通过改变多胺生物合成途径来起作用，从而抑制细胞周期和肿瘤生长。公共卫生相关性：前列腺癌是男性最常见的癌症，在美国与癌症相关的男性死亡中排名第二。在此应用中，我们将测试以下假设：饮食中的Equol可以预防或延迟前列腺的病理生长。该项目的长期目标是定义Equol抑制前列腺病理生长的机制