Green tea-mediated inhibition of aberrant DNA hypermethylation in prostate cancer

描述(由申请人提供)： 流行病学研究和实验室调查都支持绿茶在预防人类前列腺癌方面的作用。绿茶提取物(GTP)含有许多生物活性多酚化合物，这是其抗癌特性的原因。先前的研究表明，口服GTP显著降低了自发性前列腺癌转基因小鼠模型的肿瘤负担和转移，该模型被称为TRAMP。这些数据支持使用TRAMP模型来研究GTP介导的前列腺癌化学预防的分子机制。最近，绿茶多酚被发现是DNA甲基化的有效抑制剂，DNA甲基化是一种关键的致癌机制。这提示了一种新的和直接的机制来解释GTP的化学预防特性。根据这些数据，推测DNA甲基化改变参与了前列腺癌的发病机制，GTP对前列腺癌的化学预防作用是由于其能够防止或逆转异常的DNA高甲基化。为了验证这一假设，这一建议将：1)定义与TRAMP模型中前列腺癌进展一致的表观遗传学变化；以及2)确定GTP治疗对TRAMP小鼠表观遗传学参数的影响。由于前列腺癌潜伏期长，在65岁以上的男性中最常见，适度推迟进展时间的饮食干预将对前列腺癌死亡率产生深远影响。在这一点上，GTP作为前列腺癌患者的化学预防药物具有重要的实用价值。了解GTP活性的分子机制(S)对于前列腺癌化学预防试验的优化设计以及在GTP临床研究中识别新的分子生物标志物至关重要。

DESCRIPTION (provided by applicant): A role for green tea in the prevention of human prostate cancer is supported by both epidemiological studies and laboratory investigations. Green tea extract (GTP) contains a number of bioactive polyphenolic compounds that account for its anti-carcinogenic properties. Previous studies have shown that oral infusion of GTP dramatically reduces tumor burden and metastasis in a spontaneous autochthonous transgenic mouse model of prostate cancer known as TRAMP. These data support the use of the TRAMP model to examine the molecular mechanisms involved in GTP-mediated prostate cancer chemoprevention. Recently, green tea polyphenols were identified as potent inhibitors of DNA methylation, a critical oncogenic mechanism. This suggests a novel and direct mechanism to account for the chemopreventive properties of GTP. Based on these data, it is hypothesized that DNA methylation changes are involved in the etiology of TRAMP prostate cancer, and that the chemopreventive effect of GTP in TRAMP is due to its ability to prevent or reverse aberrant DNA hypermethylation. To test this hypothesis, this proposal will: 1) Define the epigenetic changes coincident with prostate cancer progression in the TRAMP model; and 2) Determine the effect of GTP treatment on epigenetic parameters in TRAMP mice. Because prostate cancer has a long latency period and is most prevalent in men over the age of 65, dietary interventions that modestly delay progression time would have a profound impact on prostate cancer death rates. In this regard, GTP has the potential for significant utility as a chemopreventive agent in prostate cancer patients. Understanding the molecular mechanism(s) responsible for the activity of GTP is essential for the optimal design of prostate cancer chemoprevention trials and for the identification of novel molecular biomarkers to follow in clinical studies of GTP.