Anti-cancer effects by the green tea catechins

描述（由申请人提供）：有有说服力的流行病学证据表明，食用膳食多酚类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表明，包括白藜芦醇、染料木素和二芳基二硫化物在内的膳食化合物在体内和体外都具有抗癌作用。绿茶及其成分多酚（儿茶素）在各种各样的实验系统中已被证明具有抗肿瘤特性。一些报道认为p53与肿瘤抑制蛋白有关，但另一些则没有。因此，绿茶诱导抗肿瘤作用的确切分子机制尚不清楚。一个有希望的机制是由儿茶素诱导细胞凋亡。事实上，已知儿茶素与诱导细胞凋亡有关。在这方面，我们对这一新提议的假设是，绿茶成分包括儿茶素（-）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）的癌症化学预防作用是通过诱导凋亡机制，包括诱导新发现的tgf - β超家族蛋白NAG-1（非甾体抗炎药激活基因）。这一假设的理论基础是：1)NAG-1基因是一种膳食诱导基因；2)NAG-1在正常结肠上皮细胞中的表达高于邻近肿瘤细胞；3)我们和其他研究小组报道的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个儿茶素或儿茶素组合在人类结直肠癌细胞中具有较高的NGA-1诱导剂。为了研究绿茶成分或其组合诱导NAG-1表达的分子机制，我们将使用两种不同的模型，HCT- 116人结直肠癌细胞和小鼠模型系统，具体目的如下：明确ECG和其他儿茶素诱导NAG-1的转录调控机制。2. 心电图治疗后基因表达谱的变化。3. 比较单用儿茶素和联合用儿茶素对结直肠癌动物模型的防治效果。

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.