Equol and Regulation of Prostate Growth

雌马酚与前列腺生长的调节

• 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
• 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

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)：该项目将确定异黄酮代谢物马酚抑制前列腺正常和病理生长的机制。在美国，前列腺癌是最常见的男性癌症，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多种因素的复杂相互作用，然而终生接触雄激素和年龄增加是两个必要的病因。同样，良性前列腺肥大(BPH)的发展也依赖于雄激素暴露，据估计，美国60岁以上的男性人口中有一半以上有BPH症状。雄激素在前列腺癌病理中的重要性从目前针对这些疾病的治疗方法中得到了证明，这些治疗方法包括减少循环中的睾酮；抑制5-α还原酶，一种合成强大雄激素二氢睾酮的酶；或阻断雄激素受体的作用。在检查前列腺癌等激素依赖型疾病的风险因素时，饮食是一个重要的考虑因素。吃东方饮食的亚洲男性的前列腺癌发病率是世界上最低的。这种相关性的基础可能是他们的饮食中存在类似雌激素的异黄酮类(染料木素和大豆苷元)。我们最近已经证明，异黄酮代谢的产物马酚也具有抗雄激素的特性。Equol选择性地结合双氢睾酮并阻止雄激素受体激活，以减少雄激素依赖的前列腺生长。马酚是大豆苷元的主要代谢物。它在高水平循环，并集中在前列腺中。此外，Equol可以选择性地与雌激素受体β结合，激活前列腺中的抗增殖级联反应。因此，Equol具有独特的双重作用，通过1)阻止雄激素的增殖作用和2)激活ERβ的抗增殖作用来抑制前列腺生长。然而，只有大约30%的人类有正确的肠道菌群来产生马兜铃醇。在这些研究中，我们将检验这样一种假设，即饮食马醇可以防止或延缓前列腺癌的病理性生长。我们还将确定Equol提供这种保护的细胞机制。这些研究利用了成年男性发生自发性前列腺癌的TRAMP小鼠系，这使得这对研究木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株注射到宿主小鼠中，并通过体内成像技术进行监测，以确定Equol对前列腺癌生长的影响。最后，我们将确定Equol是否可以通过改变多胺生物合成途径发挥作用，从而抑制细胞周期和肿瘤生长。公共卫生相关性：前列腺癌是男性中最常见的诊断癌症，在美国与癌症相关的男性死亡人数中排名第二。在这项应用中，我们将检验这样一种假设，即饮食中服用异黄酮可以防止或延缓前列腺的病理性生长，异黄酮代谢的产物具有抗雄激素和雌激素受体β激活特性。这一项目的长期目标是确定马兜铃醇抑制前列腺病理生长的机制。