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: 7738517
• 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/7738517
• 关键词: 4-hydroxyphenylacetic acid; 8-hydroxy-2' -deoxyguanosine; Acetic Acids; Adenocarcinoma; Angiogenesis Inhibition; Animals; Antioxidants; Apoptosis; Apoptotic; Asians; Biological Assay; Biological Availability; Biological Markers; Black Tea; Blood Circulation; Cell Culture Techniques; Cell Cycle Arrest; Cells; Chemoprevention; Chemopreventive Agent; Clinical; Colon; Consumption; Country; DNA Binding; Detection; Development; Diagnosis; Dose; Enzymes; Epigallocatechin Gallate; Gas Chromatography; 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; 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; 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; animal data; base; cancer cell; cell growth; design; dietary supplements; fetal bovine serum; in vivo; in vivo Bioassay; indexing; male; men; oxidative damage; phenolic acid; polyphenol; protein expression; research study; simulation

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.

绿色茶（GT）和红茶（BT）的抗癌潜力已在许多动物中得到证实， 体外细胞培养研究。茶多酚，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、改变氧化还原敏感性 信号转导途径（核因子-κ B、激活蛋白1、丝裂原活化蛋白激酶） 和抑制胰岛素样生长因子（IGF-1）导致抑制增殖，诱导 细胞凋亡、细胞周期阻滞以及抑制血管生成。然而，大多数细胞培养和动物 已经在高于人体可达到的浓度下进行了研究。目前尚不清楚是否 在动物和细胞培养研究中观察到的效果可以应用于人类研究。因此整体 本研究的目的是进行II期临床干预试验，以调查是否消耗 之前8周服用相当于6杯GT或6杯BT的绿色茶补充剂（Polypheon E） 乳腺癌切除术将降低氧化应激，改变信号通路，导致增殖抑制 以及前列腺细胞凋亡的增加。我们将使用免疫组织化学方法来确定细胞凋亡 Ki 67、Bax、Bcl-2、NFkB指标和蛋白表达以及8-羟基脱氧鸟苷浓度 人前列腺腺癌的等形态变化切片。血清前列腺特异性 抗原和IGF-1/IGFBP-3将使用荧光分析测定。由于体内多酚 和茶黄素进行广泛的内源性和结肠代谢，我们提出， 有助于GT和BT的化学预防作用。我们将使用高效液相色谱法 与Coularray电化学检测以及质谱（MS）和气相色谱/ MS， 确定多酚，茶黄素和六种不同的内源性和结肠代谢物的浓度， 我们的茶干预试验参与者的前列腺、血清和尿液中的血小板。我们还将使用 在茶干预之前和之后收集的血清在我们的LNCaP前列腺中的离体生物测定中进行测试 癌细胞最后，我们将确定六种代谢产物对细胞凋亡、Bax/Bcl-2和NF κ B-κ B的影响。 LNCaP细胞中肿瘤坏死因子α刺激后的DNA结合。结果将有助于设计 用于前列腺癌早期阶段或观察等待期间的化学预防的膳食补充剂。