Tea Polyphenols in Chemoprevention of Prostate Cancer

茶多酚对前列腺癌的化学预防作用

• 批准号: 7208668
• 负责人: Susanne Margarete Henning
• 金额: $ 26.42万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7208668
• 关键词: 4-hydroxyphenylacetic acid; 8-hydroxy-2' -deoxyguanosine; Acetic Acid; Acetic Acids; Adenocarcinoma; Angiogenesis Inhibition; Animals; Antioxidants; Apoptosis; Apoptotic; Asians; Biological Assay; Biological Availability; Biological Markers; Black Tea; Blood Circulation; Bos taurus; Cattle; Cell Cycle Arrest; Cells; Chemoprevention; Chemopreventive Agent; Clinical; Colon; Consumption; Country; Cultured Cells; DNA Binding; Daily; Detection; Development; Diagnosis; Dose; Enzymes; Epigallocatechin Gallate; Gas Chromatography; Genus Cola; Glucuronides; Goals; Green tea; Health Benefit; Hepatic; High Pressure Liquid Chromatography; Homovanillic Acid; Hour; Human; Immunohistochemistry; In Vitro; Induction of Apoptosis; Insulin-Like Growth Factor I; Intake; Intervention; Intervention Studies; Intervention Trial; Intestines; LNCaP; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Chromatography; Metabolism; Mitogen-Activated Protein Kinases; NF-kappa B; Oral; Oxidation-Reduction; Oxidative Stress; Parents; Participant; Patient observation; Phase; Placebos; Polyphenon E; Prostate; Prostate-Specific Antigen; Prostatectomy; Rate; Research Personnel; Role; Schedule; Serum; Signal Pathway; Signal Transduction Pathway; Somatomedins; Staging; Supplementation; Tea; Testing; Theaflavins; Tissues; Transcription Factor AP-1; Translating; Tumor Necrosis Factor-alpha; United States; Urine; Week; animal data; base; cancer cell; cell growth; design; dietary supplements; fetal; glucuronide; human study; in vivo; in vivo Bioassay; indexing; male; men; phenolic acid; polyphenol; protein expression; research study; simulation; theaflavin

DESCRIPTION (provided by applicant): The anticarcinogenic potential of green (GT) and black tea (BT) has been demonstrated in many animal and in vitro cell culture studies. Tea polyphenols, such as epigallocatechin gallate (EGCG) and theaflavins, inhibit cell growth through a variety of mechanisms such as antioxidant activity, alteration of redox-sensitive signal transduction pathways (nuclear factor-kappa B, activator protein 1, mitogen-activated protein kinase) and inhibition of insulin-like growth factor (IGF-1) leading to the inhibition of proliferation, induction of apoptosis, cell cycle arrest as well as inhibition of angiogenesis. However most cell culture and animal studies have been performed with higher concentrations than achievable in humans. It is not clear whether effects observed in animal and cell culture studies can be applied to human studies. Therefore, the overall goal of this study is to perform a phase II clinical intervention trial to investigate whether the consumption of a green tea supplement (Polyphenon E) equivalent to 6 cups of GT or 6 cups of BT for 8 weeks prior to prostatectomy will decrease oxidative stress, alter signaling pathways leading to an inhibition of proliferation and increase of apoptosis in the prostate. We will use immunohistochemistry to determine the apoptotic index and protein expression of Ki67, Bax, Bcl-2, NFkB and concentration of 8-hydroxydeoxyguanosine in sections of equal morphological changes of adenocarcinoma in the human prostate. Serum prostate specific antigen and IGF-1/IGFBP-3 will be determined using chemiluminescent analysis. Since in vivo polyphenols and theaflavins are subject to extensive endogenous and colonic metabolism we propose that metabolites contribute to the chemopreventive effect of GT and BT. We will use high performance liquid chromatography with coularray electrochemical detection as well as mass spectrorrietry (MS) and gas chromatography/ MS to determine the concentrations of polyphenols, theaflavins and six different endogenous and colonic metabo- lites in the prostate, serum and urine of the participants of our tea intervention trial. We will also use the serum collected before and after the tea intervention to be tested in our ex vivo bioassay in LNCaP prostate cancer cells. Finally we will determine the effect of the six metabolites on apoptosis, Bax/Bcl-2 and NFkB- DNA binding after tumor necrosis factor alpha stimulation in LNCaP cells. The results will assist in designing dietary supplements for chemoprevention of early stages of prostate cancer or during watchful waiting.

描述（由申请人提供）：绿茶（GT）和红茶（BT）的抗癌潜力已在许多动物和体外细胞培养研究中得到证实。茶多酚，例如表没食子儿茶素没食子酸酯 (EGCG) 和茶黄素，通过多种机制抑制细胞生长，例如抗氧化活性、改变氧化还原敏感信号转导途径（核因子-κ B、激活蛋白 1、丝裂原激活蛋白激酶） ）和抑制胰岛素样生长因子（IGF-1），从而抑制增殖、诱导细胞凋亡、细胞周期停滞以及抑制血管生成。然而，大多数细胞培养和动物研究的浓度都高于人类所能达到的浓度。目前尚不清楚在动物和细胞培养研究中观察到的效果是否可以应用于人类研究。因此，本研究的总体目标是进行一项II期临床干预试验，研究前列腺切除术前8周服用相当于6杯GT或6杯BT的绿茶补充剂（Polyphenon E）的摄入量是否会减少氧化应激，改变信号通路，导致前列腺增殖抑制和细胞凋亡增加。我们将采用免疫组织化学法测定人前列腺腺癌等形态变化切片中Ki67、Bax、Bcl-2、NFkB的凋亡指数和蛋白表达以及8-羟基脱氧鸟苷的浓度。将使用化学发光分析测定血清前列腺特异性抗原和IGF-1/IGFBP-3。由于体内多酚和茶黄素受到广泛的内源性和结肠代谢，我们认为代谢物有助于 GT 和 BT 的化学预防作用。我们将使用配备coularray电化学检测的高效液相色谱以及质谱（MS）和气相色谱/MS来测定前列腺、血清和尿液中的多酚、茶黄素和六种不同的内源性和结肠代谢物的浓度。我们的茶干预试验的参与者。我们还将使用茶干预前后收集的血清在 LNCaP 前列腺癌细胞的离体生物测定中进行测试。最后，我们将确定 LNCaP 细胞中肿瘤坏死因子 α 刺激后六种代谢物对细胞凋亡、Bax/Bcl-2 和 NFkB-DNA 结合的影响。研究结果将有助于设计膳食补充剂，用于前列腺癌早期阶段或观察等待期间的化学预防。