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，持续性慢性炎症在前列腺癌发生中很重要。从炎症细胞释放的活性氧和氮种在增殖上皮中诱导氧化应激，这些氧气可以直接与DNA相互作用，从而通过激活转录因子复杂，NFKAPPAB，在信号过程中产生永久性基因组改变和/或起关键作用，作为调节介体的关键作用。 Rel/NF-Kappab家族控制的重要基因网络的成员，这些网络影响细胞增殖，炎症，细胞粘附，凋亡和对细胞氧化还原平衡变化的适应性反应。异常的NFKappab激活与几种人类恶性肿瘤的发病机理有关。我们最近的研究（Neoplasia vol.6 No.4，2004年）表明，NF-kappab/p65在人类前列腺腺癌中被组成式激活，并且与疾病进展相关。根据这些有趣的发现，我们建议NF-kappab信号通路是开发针对前列腺癌的预防和/或治疗策略的关键分子靶标。本提案利用了这些新颖的发现，旨在研究洋甘菊的抗炎，抗氧化剂和癌症化学预防潜力（一种常见的草药，用作民间医学），通过靶向NF-kappab信号传导途径。最近，对洋甘菊作为互补和替代医学（CAM）的发展兴趣是由于其抗炎，抗氧化剂和轻度镇静特性所致。洋甘菊是最受欢迎的草药之一，其形式相当于每天超过100万杯。具体目的1-4将研究洋甘菊的分子机制，该机制可以直接导致NF-kappab及其在前列腺癌进展中重要的反应基因（Cyclin d1，bcl2，bclxl，bclxl，il-6，il-6，il-8，iL-8，iL-8，mmp-9和par4）;和/或间接通过i）ROS产生，ii）炎症基因的转录调控（COX-2和NOS-2），iii）γ-谷氨基半胱氨酸合成酶启动子的反式激活以及iv）NRF2/NRF2/均依赖于雄激素敏感 - 敏感 - 敏感的人类人类甲循环细胞。我们还将研究洋甘菊如何通过分析关键激酶分子的水平和活性以及与NF-kappab信号通路有关的关键激酶分子的水平和活性来介导这些影响。此外，我们将采用遗传（过表达和抑制。技术）和药理学方法（抑制剂）方法来描述洋甘菊的作用是否是由NF-kappab的下调直接介导的。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，我们还建议在良好的转基因小鼠模型中测试洋甘菊的癌症化学预防潜力，这些模型在前列腺癌进展过程中表现出明显较高的构成型NF-kappab/p65表达。拟议研究的完成将提供“头开始”，以开始前列腺癌患者和/或高危人群的临床试验。