Equol and Regulation of Prostate Growth

雌马酚与前列腺生长的调节

• 批准号: 8125052
• 负责人: Robert J Handa
• 金额: $ 30.61万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125052
• 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 Prostatic Hypertrophy; Binding; Biological Assay; Cell Cycle; Cell Line; Cell Proliferation; 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; Health; 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; 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; Time; Tissues; Transfection; Transgenic Mice; United States; Viral; 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; small hairpin RNA; tumor; tumor growth; tumor progression

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）：本项目将确定雌马酚（一种代谢物）抑制前列腺正常和病理生长的机制。在美国，前列腺癌是男性中最常见的癌症，在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，然而终生暴露于雄激素和年龄增长是两个必要的病因因素。类似地，良性前列腺肥大（BPH）的发展也依赖于雄激素暴露，并且据估计，美国超过一半的60岁以上的男性人口具有BPH的症状。雄激素在前列腺病理学中的重要性通过这些疾病的当前疗法得到证明，所述疗法包括减少循环睾酮;抑制5-α还原酶（一种合成强效雄激素双氢睾酮的酶）;或阻断雄激素受体的作用。在检查前列腺癌等依赖饮食的疾病的风险因素时，饮食是一个重要的考虑因素。亚洲男性，在东方饮食，有前列腺癌的发病率最低的世界。这种相关性的基础可能是在他们的饮食中存在雌激素样黄酮（染料木黄酮和大豆黄酮）。我们最近发现雌马酚，一种代谢产物，也有抗雄激素的特性。雌马酚选择性结合二氢睾酮，阻止雄激素受体激活，减少雄激素依赖性前列腺生长。雌马酚是大豆苷元的主要代谢产物。它以高水平循环，并集中在前列腺。此外，雌马酚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级联反应。因此，雌马酚具有独特的双重作用，通过1）防止雄激素的增殖作用和2）激活ER β的抗增殖作用来抑制前列腺生长。然而，只有大约30%的人具有正确的肠道植物群来产生雌马酚。在这些研究中，我们将检验这一假设，即饮食雌马酚可以预防或延缓前列腺的病理性生长。我们还将确定雌马酚提供这种保护的细胞机制。这些研究利用TRAMP小鼠系，其中自发性前列腺肿瘤在成年雄性中发展，使得这对于研究雌马酚的化学预防作用特别有用。此外，我们将利用原位注射模型，将表达荧光素酶报告基因的人前列腺癌细胞系注射到宿主小鼠中，并通过体内成像技术进行监测，以确定雌马酚对前列腺肿瘤生长的影响。最后，我们将确定雌马酚是否可以通过改变多胺生物合成途径，从而抑制细胞周期和肿瘤生长。公共卫生相关性：前列腺癌是男性中最常见的癌症，在美国与癌症相关的男性死亡中排名第二。在本申请中，我们将检验这样的假设，即前列腺的病理性生长可以通过饮食给予雌马酚来预防或延迟，雌马酚是一种具有抗雄激素和雌激素受体β激活特性的β代谢产物。这个项目的长期目标是确定雌马酚抑制前列腺病理性生长的作用机制