Chamomile as Medicine for Prostate cancer

洋甘菊作为治疗前列腺癌的药物

基本信息

批准号：
7285702
负责人：
SANJAY GUPTA
金额：
$ 26.55万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-15 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7285702
关键词：
26S proteasome Adenocarcinoma Age American Association of Cancer Research Androgens Animal Model Animals Anti-Bacterial Agents Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apigenin Apoptosis Apoptotic Area Atrophic Binding Biological Breast Cancer Patient Cell Adhesion Cell Culture System Cell Death Cell Nucleus Cell Proliferation Cell Survival Cells Cessation of life Chamomile Chamomile extract Chemopreventive Agent Chronic Clinical Clinical Trials Colon Complementary Medicine Complementary and alternative medicine Complex Confounding Factors (Epidemiology)Culture Media Cyclin D1 DNA DNA Binding DNA Fragmentation Data Development Diagnosis Diet Dietary Intervention Disease Disease Progression Dissociation Down-Regulation Drug Metabolic Detoxication EP300 gene Early Diagnosis Effectiveness of Interventions Enzyme-Linked Immunosorbent Assay Enzymes Epidemiologic Studies Epidemiology Epithelial Epithelial Cells Epithelium Equilibrium Esophagus Etiology Evaluation Event Exhibits Family Flavonoids Folk Medicine Fright Gelatinase B Gene Activation Generations Genes Genetic Genetic Transcription Genomics Genus Cola Glutamate-Cysteine Ligase Glutathione Glutathione S-Transferase Head Start Program Herb Human IL8 gene Immune In Vitro Individual Induction of Apoptosis Inflammation Inflammatory Insulin-Like Growth Factor Binding Protein 3 Insulin-Like Growth Factor I Interleukin-6 Intervention JNK-activating protein kinase Label Laboratory Study Lead Literature Lung Lymphocyte MAPK14 gene Magnetic Resonance Imaging Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of prostate Matrix Metalloproteinases Mediating Mediator of activation protein Medicine Methods Micronutrients Mitogen-Activated Protein Kinase Kinases Modeling Molecular Molecular Target Monitor Mus N-terminal NAD(P)H dehydrogenase (quinone) 1, human NOS2A gene NQO1 gene Neoplasm Metastasis Neoplasms Nitrogen Non-Invasive Cancer Detection Nuclear Nuclear Translocation Oncogenes Oxidation-Reduction Oxidative Stress Oxygen PAWR gene PCNA gene PTGS2 gene Pancreas Pathogenesis Pathway interactions Patient observation Patients Phase Phenotype Phosphorylation Phosphotransferases Plant Preparations Plants Play Prevention Preventive Principal Investigator Process Production Proliferating Property Prostate Prostate Adenocarcinoma Prostate Cancer therapy Prostate carcinoma Prostatic Intraepithelial Neoplasias Prostatic Neoplasms Publishing Radiation Radiosurgery Recurrence Regulation Relative (related person)Research Personnel Resistance Risk Role Serine Serum Signal Pathway Signal Transduction Pathway Site Skin Source Stimulus Stress Tea Testing Therapeutic Therapeutic Agents Therapeutic Effect Tissues Transactivation Transcription Coactivator Transcriptional Activation Transcriptional Regulation Transgenic Organisms Ulcer United States Volatile Oils Week Work Wound Healing activating transcription factor annexin A5 aqueous base c-myc Genes cancer type carcinogenesis cell growth cell injury cell type computerized data processing cytokine day design drinking water gamma-glutamylcysteine hormone therapy human NOS2A protein in vivo inhibitor/antagonist interest male member men mouse model neoplastic cell novel nutrition p65 prevent programs promoter research study response sedative transcription factor tumor growth tumor progression upstream kinase

项目摘要

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.

描述（由申请人提供）：流行病学研究和临床观察表明，持续的慢性炎症在前列腺癌发生中很重要。炎症细胞释放的活性氧和氮在增殖的上皮中诱导氧化应激，氧化应激可以直接与 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物 NFkappaB 在信号传导过程中作为调节介质发挥关键作用。 Rel/NF-kappaB 家族的成员控制重要的基因网络，影响细胞增殖、炎症、细胞粘附、细胞凋亡以及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（Neoplasia Vol.6 No.4，2004）表明，NF-kappaB/p65 在人类前列腺腺癌中持续激活，并与疾病进展相关。基于这些有趣的发现，我们建议 NF-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 信号通路来研究洋甘菊（一种用作民间药物的常见草药）的抗炎、抗氧化和癌症化学预防潜力。最近人们对将洋甘菊开发为前列腺癌的补充和替代医学 (CAM) 感兴趣，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，每天以茶的形式饮用的量超过一百万杯。具体目标 1-4 将研究洋甘菊可直接抑制 NF-kappaB 及其在前列腺癌进展中重要的反应基因（细胞周期蛋白 D1、Bcl2、BclxL、IL-6、IL-8）的分子机制。、MMP-9 和 PAR4)；和/或间接通过 i) ROS 产生，ii) 炎症基因（COX-2 和 NOS-2）的转录调节，iii) γ-谷氨酰半胱氨酸合成酶启动子的反式激活，以及 iv) 雄激素敏感的 Nrf2/ARE 依赖性解毒作用- 和不敏感的 - 人类前列腺癌细胞。我们还将通过分析关键激酶分子的水平和活性以及参与 NF-kappaB 信号通路的相关机制，研究洋甘菊如何通过下调 NF-kappaB 来介导这些作用。此外，我们将采用遗传（过度表达和抑制技术）和药理学（抑制剂）方法来确定洋甘菊的作用是否直接由 NF-kappaB 的下调介导。这些结果将与从正常人前列腺上皮细胞获得的结果进行比较。此外，我们还建议在一个完善的转基因小鼠模型 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着更高的 NF-kappaB/p65 组成型表达。拟议研究的完成将为在前列腺癌患者和/或高危个体中启动临床试验提供“先机”。