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.

植物性膳食补充剂被消费者用于预防和治疗前列腺癌。最近， 动物前列腺癌模型已经对这些补充剂的安全性和有效性进行了测试。我们 建立了转基因小鼠前列腺癌(TRAMP)小鼠的克隆，雌激素 受体缺陷(ERaKO和ER(3K0))小鼠，以及表达traMP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小鼠对PDC(可怜)具有高度保护 前列腺癌)和ERpKO小鼠对PDC高度敏感。此外，我们 最近发现植物雌激素、植物甾醇和氧化甾醇可以抑制刺猬信号，a 前列腺癌的重要途径。令人惊讶的是，我们发现氧合甾醇可以更好地结合ERP 10OX 比Era的Kd为~20 nm。我们的总体假设是差异调节BV5植物及其 抗氧化剂/植物雌激素/植物甾醇成分，其作用是通过5kev通路介导的 有效预防和治疗前列腺癌。要检查的5keV路径波是 抗氧化剂(Nrf2/Keap1和NADPH氧化酶)途径及其与核因子-kappaB-的相互作用。 雌激素和刺猬信号通路波。我们的目标是描述关键的前列腺肿瘤的反应。 这些植物药物的生物标志物，并为这些反应提供新的分子机制 进行后来的临床试验。目的1：体外测定5种抗癌药物对前列腺癌细胞的作用 植物药和选定的纯化合物对活性、蛋白质浓度和mRNAs的影响 5个关键途径：目标2：在单转基因和双转基因流浪汉中进行体内癌症预防试验 小鼠测试一些纯化合物和植物药的防癌活性是否会依赖于 Keap1/Nrf2和Hedgehog途径组件；目标3：测试潜在的活性成分和复合体 AIMS#1或AIMS#2的植物提取物，其成分与体内人体异种移植的成分相同 前列腺癌模型；以及目标4：确定与细胞增殖、分化、 前列腺组织中的细胞凋亡和体内对植物药反应的五条关键通路与这些相关 与肿瘤形成的反应，并继续与氧化剂的成分相关， 炎症、刺猬和/或雌激素途径。这些研究将为以下方面提供基本见解 前列腺癌生物学，并帮助提供生物标志物，以评估这些植物药物在改变 人类前列腺癌的发生和发展。