Anti-cancer effects by the green tea catechins

描述（由申请人提供）：有令人信服的流行病学证据表明，食用多酚植物衍生化合物可减少慢性疾病，如癌症。包括我们在内的许多实验室研究已经显示了膳食化合物包括白藜芦醇、染料木素和二芳基二硫化物在体内和体外对致癌作用的抑制作用。绿色茶及其成分多酚（儿茶素）已被证明在各种各样的实验系统中具有抗肿瘤特性。一些报告表明p53肿瘤抑制蛋白的参与，但其他人没有。因此，绿色茶诱导抗肿瘤作用的确切分子机制尚不清楚。一个有前途的机制是儿茶素诱导细胞凋亡。事实上，已知儿茶素与细胞凋亡的诱导有关。在这方面，我们对这一新提议的假设是，包括儿茶素（-）表没食子儿茶素3-没食子酸酯（EGCG）、表儿茶素没食子酸酯（ECG）、表没食子儿茶素（EGC）和表儿茶素（EC）的绿色茶组分的癌症化学预防作用是通过诱导凋亡机制实现的，所述凋亡机制涉及诱导新鉴定的TGF-β超家族蛋白NAG-1（非甾体抗炎药活化基因）。这一假说的理论基础是：1）NAG-1基因被鉴定为饮食诱导基因，2）NAG-1在正常结肠上皮中的表达高于邻近的肿瘤细胞，3）NAG-1具有促凋亡和抗肿瘤活性。因此，本项目的总体目标是鉴定单一儿茶素或儿茶素组合在人结直肠癌细胞中的更高NGA-1诱导剂。为了研究绿色茶成分或它们的组合诱导NAG-1表达的分子机制，我们将使用两种不同的模型，HCT- 116人结直肠腺癌细胞和小鼠模型系统，具体目的如下：1.定义负责ECG和其他儿茶素诱导NAG-1的转录调节机制。2.心电图治疗后基因表达谱的变化。3.在结直肠癌动物模型中比较单独和组合儿茶素的预防和治疗效果。

DESCRIPTION (provided by applicant): There is persuasive epidemiological evidence that consumption of dietary polyphenolic plant-derived compounds reduce chronic disease such as cancer. Many laboratory studies including us have shown the inhibitory effect of dietary compounds including resveratrol, genistein, and diaryl disulfide against carcinogenesis in vivo and in vitro. Green tea and its constituent polyphenols (catechins) have been shown to possess anti-tumor properties in a wide variety of experimental systems. Some reports are suggesting an involvement of p53 tumor suppressor proteins, but others do not. Thus, the exact molecular mechanism by which green tea induce anti-tumorigenic effect is not clear. One promising mechanism is the induction of apoptosis by catechins. Indeed, catechins have been known to be associated with the induction of apoptosis. In this regard, our hypothesis of this novel proposal is that the cancer chemopreventive effect of green tea components including catechin (-) epigallocatechin 3-gallate (EGCG), epicatechin gallate (ECG), epigallocatechin (EGC), and epicatechin (EC) is through the induction of apoptotic mechanisms involving the induction of a newly identified TGF-beta superfamily protein, NAG-1 (Nonsteroidal anti-inflammatory drug activated gene). The rationale for this hypothesis is based on the followings: 1) identification of the NAG-1 gene as a dietary induced gene, 2) higher NAG-1 expression in normal colonic epithelial than adjacent tumor cells, 3) NAG-1 has pro-apoptotic and anti-tumorigenic activities reported by us and other groups. Therefore, the overall goal of this project is to identify single catechins or the combinations of catechins for higher NGA-1 inducer in human colorectal cancer cells. To investigate the molecular mechanisms of which a green tea component or combination of them induces NAG-1 expression, we will use two different models, HCT- 116 human colorectal adenocarcinoma cells and mouse model system with following specific aims: 1. Define transcriptional regulatory mechanisms responsible for NAG-1 induction by ECG and other catechins. 2. Profile changes in gene expression following ECG treatment. 3. Compare the preventative and therapeutic efficacy of individual and combination catechins in animal models of colorectal cancer.