Chamomile as Medicine for Prostate cancer

描述(由申请人提供)：流行病学研究和临床观察表明，持续性慢性炎症在前列腺癌的发生中很重要。炎症细胞释放的活性氧和氮物质可以直接与DNA相互作用，产生永久性的基因组改变和/或通过激活转录因子复合体NFkappaB在信号传递过程中发挥关键作用，从而诱导增殖的上皮细胞产生氧化应激。Rel/NF-kappaB家族的成员控制着重要的基因网络，这些基因网络影响细胞增殖、炎症、细胞黏附、细胞凋亡和对细胞氧化还原平衡变化的适应性反应。NFkappaB的异常激活与多种人类恶性肿瘤的发病机制有关。我们最近的研究表明，核因子-kappaB/p65在前列腺癌中被结构性激活，并与疾病进展相关。基于这些有趣的发现，我们建议将核因子-kappaB信号通路作为开发前列腺癌预防和/或治疗策略的关键分子靶点。本提案利用这些新发现，旨在通过靶向NF-kappaB信号通路来研究民间常用草本植物洋甘菊的抗炎、抗氧化和癌症化学预防潜力。近年来，人们对洋甘菊作为前列腺癌的补充和替代药物(CAM)的开发感兴趣，这是因为它具有抗炎、抗氧化和温和的镇静特性。洋甘菊是最受欢迎的草药之一，以茶的形式食用，每天相当于100多万杯。具体目标1-4将研究洋甘菊的分子机制(S)，它可以直接导致抑制NF-kappaB及其在前列腺癌进展中至关重要的反应基因(细胞周期蛋白D1、Bcl2、BclxL、IL-6、IL-8、MMP9和PAR4)；和/或间接地通过i)ROS产生，ii)炎症基因(COX-2和NOS-2)的转录调控，III)伽马-谷氨酰半胱氨酸合成酶启动子的反式激活，以及iv)NRF2/ARE依赖的解毒。我们还将通过分析参与NF-kappaB信号通路的关键激酶分子的水平和活性以及相关机制，来研究洋甘菊如何通过下调NF-kappaB来调节这些效应。此外，我们将使用遗传学(过度表达和抑制技术)和药理学(抑制剂)方法来描述洋甘菊的作用是否直接通过下调NF-kappaB来介导。这些结果将与从正常人类前列腺上皮细胞获得的结果进行比较。此外，我们还建议在已建立的转基因小鼠模型TRAMP中测试洋甘菊的癌症化学预防潜力，该模型在前列腺癌进展过程中表现出显著高的结构性核因子-kappaB/p65表达。拟议研究的完成将为启动前列腺癌患者和/或高危个体的临床试验提供“先行一步”。

DESCRIPTION (provided by applicant): Epidemiological studies and clinical observations suggest that persistent chronic inflammation is important in prostate carcinogenesis. The reactive oxygen and nitrogen species released from inflammatory cells induce oxidative stress in the proliferating epithelium that could directly interact with DNA to produce permanent genomic alterations and/or play critical role as regulatory mediators in signaling processes by activating transcription factor complex, NFkappaB. Members of the Rel/NF-kappaB family control important network of genes that influence cell proliferation, inflammation, cellular adhesion, apoptosis and adaptive responses to changes in cellular redox balance. Aberrant NFkappaB activation has been implicated in the pathogenesis of several human malignancies. Our recent studies (Neoplasia Vol.6 No.4, 2004) have shown that NF-kappaB/p65 is constitutively activated in human prostate adenocarcinoma and correlates with disease progression. Based on these interesting findings we suggest NF-kappaB signaling pathway as a key molecular target for the development of preventive and/or therapeutic strategies against prostate cancer. The present proposal capitalizes on these novel findings and is designed to investigate the antiinflammatory, antioxidant and cancer chemopreventive potential of chamomile, a common herb used as folk medicine, by targeting NF-kappaB signaling pathway. Recent interest in the development of chamomile as complementary and alternative medicine (CAM) for prostate cancer is due to its anti-inflammatory, antioxidant and mild sedative properties. Chamomile is one of the most popular herbs consumed in the form of tea equivalent to over one million cups per day. The specific aims 1-4 will investigate the molecular mechanism(s) of chamomile that can directly lead to inhibition of NF-kappaB and its responsive genes important in prostate cancer progression (cyclin D1, Bcl2, BclxL, IL-6, IL-8, MMP- 9, and PAR4); and/or indirectly through i) ROS production, ii) transcriptional regulation of inflammatory genes (COX-2 and NOS-2), iii) transactivation of gamma-glutamylcysteine synthetase promoter, and iv) Nrf2/ARE-dependent detoxification in both androgen sensitive- and insensitive- human prostate carcinoma cells. We will also investigate how chamomile can mediate these effects through down-regulation of NF-kappaB by analyzing levels and activity of key kinase molecules and associated mechanisms that are involved in the NF-kappaB signaling pathway. Moreover, we will employ genetic (over-expression and suppression.techniques) and pharmacological (inhibitors) approaches to delineate whether the effects of chamomile are directly mediated by the down regulation of NF-kappaB. These results will be compared to those obtained from normal human prostate epithelial cells. Additionally, we also propose to test the cancer chemopreventive potential of chamomile in a well established transgenic mouse model, TRAMP that exhibit significantly higher constitutive NF-kappaB/p65 expression during prostate cancer progression. Completion of the proposed studies will provide a 'head start' to initiate clinical trials in prostate cancer patients and/or high-risk individuals.