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

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的转基因腺癌（TRAMP）小鼠的集落，雌激素 受体缺陷型（ERaKO和ER（3K0））小鼠和表达TRAMP转基因的ER缺陷型小鼠。 来自我们的模型的令人兴奋的数据清楚地表明，ERaKO小鼠对PDC具有高度的保护作用（缺乏免疫原性）。 分化癌）和ERpKO小鼠对PDC高度易感。另外我们 最近发现植物雌激素、植物甾醇和氧化甾醇可以抑制hedgehog信号， 前列腺癌的早期症状令人惊讶的是，我们发现氧固醇可以更好地结合ERp 10OX， 比ER α的Kd约为20 nM。我们的总体假设是，5种植物及其 抗氧化剂/植物雌激素/植物甾醇组分，其作用由5keV途径介导，将被 有效预防和治疗前列腺癌。要检查的5 kev路径波是 （抗）氧化剂（Nrf2/Keap1和NADPH氧化酶）途径及其与NF-κ B-的相互作用。 雌激素和刺猬信号通路。我们的目标是描述关键前列腺肿瘤 本发明的目的是提供这些植物的生物标志物，并为这些反应提供新的分子机制， 进行后期临床试验。目的1：体外测定5种药物对前列腺癌细胞系的作用 植物和选择的纯化合物对活性，蛋白质浓度和mRNA表达的影响， 5个关键途径：目标2：在单和双转基因TRAMP中进行体内癌症预防试验 小鼠来测试一些纯化合物和植物的癌症保护活性是否依赖于 Keap 1/Nrf 2和hedgehog途径组分;目标3：测试潜在的活性成分和复合物 来自目的#1或#2的植物提取物，其具有在更快的体内人异种移植中使用的相同成分 前列腺癌模型;和目的4：鉴定与细胞增殖，分化， 细胞凋亡和体内前列腺组织中响应植物药的五个关键途径，将这些 与肿瘤发生的反应，并继续与氧化剂的成分， 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，并帮助提供生物标志物，以评估这些植物在修改前列腺肿瘤生物学中的作用。 人类前列腺肿瘤的发病率和进展。

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.