Tea Polyphenols in Chemoprevention of Prostate Cancer

茶多酚对前列腺癌的化学预防作用

基本信息

批准号：
7991343
负责人：
Susanne Margarete Henning
金额：
$ 25.63万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7991343
关键词：
8-hydroxy-2&apos -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 Binding Protein 3 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 TNF gene 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

项目摘要

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.

绿茶 (GT) 和红茶 (BT) 的抗癌潜力已在许多动物和动物身上得到证实。体外细胞培养研究。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、改变氧化还原敏感性信号转导途径（核因子-kappa 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、细胞周期停滞以及血管生成的抑制。然而大多数细胞培养物和动物研究中的浓度高于人类所能达到的浓度。目前还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，总体本研究的目标是进行 II 期临床干预试验，以调查是否食用绿茶补充剂（Polyphenon E）相当于 6 杯 GT 或 6 杯 BT，持续 8 周前列腺切除术将减少氧化应激，改变信号通路，从而抑制增殖和前列腺细胞凋亡的增加。我们将使用免疫组织化学来确定细胞凋亡 Ki67、Bax、Bcl-2、NFkB 指数及蛋白表达量及 8-羟基脱氧鸟苷浓度人类前列腺腺癌的相同形态变化的切片。血清前列腺特异性抗原和IGF-1/IGFBP-3将使用化学发光分析来确定。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。我们将使用高效液相色谱法通过 coularray 电化学检测以及质谱 (MS) 和气相色谱/ MS 来确定多酚、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、血清和尿液中含有 lites。我们还将使用茶干预前后收集的血清将在 LNCaP 前列腺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物对细胞凋亡的影响，Bax/Bcl-2和NFkB- LNCaP 细胞中肿瘤坏死因子 α 刺激后 DNA 结合。结果将有助于设计用于对前列腺癌早期阶段或观察等待期间进行化学预防的膳食补充剂。