Tea Polyphenols in Chemoprevention of Prostate Cancer

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。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，如抗氧化活性、氧化还原敏感性的改变等 信号转导途径(核因子-kappaB、激活蛋白1、丝裂原活化蛋白激酶) 而抑制胰岛素样生长因子(IGF-1)导致抑制细胞增殖、诱导 细胞凋亡、细胞周期停滞以及血管生成的抑制。然而，大多数细胞培养和动物 研究的浓度比在人类身上可以达到的浓度更高。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也可以应用于人类研究。因此，总体来说， 这项研究的目标是进行一项II期临床干预试验，以调查 服用前8周相当于6杯GT或6杯BT的绿茶补充剂(多酚E) 前列腺切除术将减少氧化应激，改变导致增殖抑制的信号通路 并增加了前列腺细胞的凋亡率。我们将用免疫组织化学的方法来确定细胞的凋亡 Ki67、Bax、Bcl2、NFkB的表达及8-羟基脱氧鸟苷浓度的变化 人前列腺癌等形态切片。血清前列腺特异性 抗原和IGF-1/IGFBP-3将用化学发光法测定。由于体内多酚类物质 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 用库拉雷电化学检测、质谱仪(MS)和气相色谱/质谱仪(GC/MS)对 测定茶多酚、茶黄素和6种不同内源性及结肠代谢产物的浓度。 我们茶干预试验参与者的前列腺、血清和尿液中的滴度。我们还将使用 TEA干预前后采集的血清用于我们的LNCaP前列腺体外生物测定 癌细胞。最后，我们将确定六种代谢物对细胞凋亡、Bax/Bcl2和NFkB-2的影响。 肿瘤坏死因子α刺激后LNCaP细胞的DNA结合。研究结果将有助于设计 对前列腺癌早期阶段或在警惕等待期间进行化学预防的膳食补充剂。

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.