Botanicals Targeting 5 Signaling Pathways to prevent prostate cance/Dennis Lubahn

针对预防前列腺癌的 5 种信号通路的植物药/Dennis Lubahn

• 批准号: 8007164
• 负责人: DENNIS B LUBAHN
• 金额: $ 35.82万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8007164
• 关键词: Adenocarcinoma; Age; American; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Appearance; Arts; Binding; Bioinformatics; Biological Markers; Botanicals; Cancer Model; Cancer Prevention Trial; Carcinoma; Cell Culture System; Cell Proliferation; Cells; Chemopreventive Agent; Clinical Trials; Complex; Consumption; Data; Dietary Factors; Disease Progression; Dose; Elderberry; Endocrine; Ensure; Erinaceidae; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Event; Future; Genetic; Genetic Predisposition to Disease; Goals; Gold; Health Care Costs; Human; In Vitro; Incidence; Inflammatory; Knock-out; Knockout Mice; LNCaP; Life; Longevity; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Medicine; Messenger RNA; Metabolism; Modeling; Molecular; Molecular Profiling; Mus; NADPH Oxidase; NF-kappa B; Oxidants; PC3 cell line; Pathway interactions; Phase II Clinical Trials; Phenotype; Phytoestrogens; Phytosterols; Plants; Prevalence; Prostate; Prostatic Neoplasms; Proteins; Quality of life; Regulation; Research; Role; Safety; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Staging; Testing; Time; Tissues; Transgenes; Transgenic Model; Transgenic Organisms; Tumor Biology; Wild Type Mouse; Work; Xenograft Model; Xenograft procedure; animal tissue; anticancer activity; cancer cell; cancer prevention; dietary supplements; estrogenic activity; immune function; in vivo; inhibitor/antagonist; insight; knockout animal; men; mouse model; neoplastic cell; novel; prevent; prostate cancer prevention; response; smoothened signaling pathway; soy; tool; tumor; tumor progression; tumorigenesis

Botanical dietary supplements are used by consumers to prevent and to treat prostate cancer. Recently, an animal prostate cancer model has allowed the safety and efficacy of these supplements to be tested. We have established colonies of TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, estrogen receptor-deficient (ERaKO and ER(3K0) mice, and ER-deficient mice expressing the TRAMP transgene. Exciting data from our model clearly show that ERaKO mice are highly protected against PDC (poorty differentiated carcinoma) ofthe prostate and ERpKO mice are highly susceptible to PDC. In addition, we recently have found that phytoestrogens, phytosterols, and oxysterols can inhibit hedgehog signaling, a pathway important in prostate cancer. And surprisingly we find that oxysterols can bind ERp 10OX better than ERa with a Kd of ~20nM. Our overall hvpothesis is that differential regulation bv 5 botanicals and their antioxidant/phytoestrogen/phvtosterol components, whose actions are mediated bv 5 kev pathwavs, will be effective in prostate cancer prevention and treatment. The 5 kev pathwavs to be examined are the (anti)oxidant(Nrf2/Keap1 and NADPH oxidase) pathwavs and their interactions with the NF-kappaB-. estrogen-, and hedgehog-signaling pathwavs. Our goals are to characterize responses of key prostate tumor biomarkers to these botanicals and to provide novel molecular mechanisms for these responses useful in conducting later clinical trials. Aim 1: Determine in vitro in prostate cancer cell lines the effects ofthe 5 botanicals and selected pure compounds on the activities, protein concentrations, and mRNAs expressed in 5 key pathwavs: Aim 2: Perform in vivo cancer prevention trials in single and double transgenic TRAMP mice to test if the cancer protective activity of some pure compounds and botanicals will be dependent upon Keap1/Nrf2 and hedgehog pathway components; Aim 3: Test potential active ingredients and complex botanical extracts from Aims #1 or #2 with the same ingredients used in much faster in vivo human xenograft models of prostate cancer; and Aim 4: Identify responses associated with cell proliferation, differentiation, apoptosis, and the five key pathways in vivo in prostate tissues in response to botanicals, correlate these responses with tumorigenesis, and continue the correlations with the components ofthe oxidant, inflammatory, hedgehog, and/or estrogen pathways. These studies will provide fundamental insights into prostate tumor biology, and help provide biomarkers to assess the role of these botanicals in modifying the incidence and progression of prostate tumors in humans.

消费者使用植物饮食补充剂来预防和治疗前列腺癌。最近， 动物前列腺癌模型允许测试这些补充剂的安全性和功效。我们 已经建立了小鼠前列腺（流浪汉）小鼠的转基因腺癌​​的菌落 受体缺陷（Erako和ER（3K0）小鼠，以及表达流浪汉转基因的ER缺陷小鼠。 来自我们模型的令人兴奋的数据清楚地表明，Erako小鼠受到PDC的高度保护（Poorty 前列腺和ERPKO小鼠的分化癌极易受到PDC的影响。另外，我们 最近发现，植物雌激素，植物醇和氧甲醇可以抑制刺猬信号，A 对前列腺癌很重要的途径。出乎意料的是，我们发现氧甲醇可以更好地结合ERP 10ox 比时代的KD约为20nm。我们的总体HVPothesis是，差异调节BV 5植物及其 抗氧化剂/植物雌激素/PHVTosterol成分的作用是介导的BV 5 KeV Pathwavs 有效预防前列腺癌。要检查的5个kev pathwav是 （抗）氧化剂（NRF2/KEAP1和NADPH氧化酶）途径及其与NF-kappab-的相互作用。 雌激素和刺猬信号路径。我们的目标是表征关键前列腺肿瘤的反应 这些植物学的生物标志物，并为这些反应提供新的分子机制 进行后来的临床试验。 AIM 1：确定前列腺癌细胞系的体外效果5 植物性和选择的纯化合物在活动中表达的活动，蛋白质浓度和mRNA 5个关键路径：目标2：在单一和双转基因流浪汉中进行体内癌症预防试验 小鼠测试某些纯化合物和植物药的癌症保护活性是否取决于 KEAP1/NRF2和刺猬途径组件； AIM 3：测试潜在的活性成分和复合物 AIMS＃1或＃2的植物提取物与体内异种移植物中使用的相同成分相同 前列腺癌模型；目标4：确定与细胞增殖，分化相关的反应， 凋亡和前列腺组织中五个关键途径响应植物学，将其相关 肿瘤发生的反应，并继续与氧化剂的成分相关， 炎症，刺猬和/或雌激素途径。这些研究将提供基本的见解 前列腺肿瘤生物学，并有助于提供生物标志物来评估这些植物学在修改中的作用 人类前列腺肿瘤的发生率和进展。