Adhami Vaqar M, Ahmad Nihal, Mukhtar Hasan
Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA.
J Nutr. 2003 Jul;133(7 Suppl):2417S-2424S. doi: 10.1093/jn/133.7.2417S.
Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer-related deaths in American males. For these reasons, it is necessary to intensify our efforts for better understanding and development of novel treatment and chemopreventive approaches for this disease. In recent years, green tea has gained considerable attention as an agent that could reduce the risk of several cancer types. The cancer-chemopreventive effects of green tea appear to be mediated by the polyphenolic constituents present therein. Based on geographical observations that suggest that the incidence of PCa is lower in Japanese and Chinese populations that consume green tea on a regular basis, we hypothesized that green tea and/or its constituents could be effective for chemoprevention of PCa. To investigate this hypothesis, we initiated a program for the chemoprevention of PCa by green tea. In cell-culture systems that employ human PCa cells DU145 (androgen insensitive) and LNCaP (androgen sensitive), we found that the major polyphenolic constituent (-)-epigallocatechin-3-gallate (EGCG) of green tea induces 1) apoptosis, 2) cell-growth inhibition, and 3) cyclin kinase inhibitor WAF-1/p21-mediated cell-cycle dysregulation. More recently, using a cDNA microarray, we found that EGCG treatment of LNCaP cells results in 1) induction of genes that functionally exhibit growth-inhibitory effects, and 2) repression of genes that belong to the G-protein signaling network. In animal studies that employ a transgenic adenocarcinoma of the mouse prostate (TRAMP), which is a model that mimics progressive forms of human prostatic disease, we observed that oral infusion of a polyphenolic fraction isolated from green tea (GTP) at a human achievable dose (equivalent to 6 cups of green tea/d) significantly inhibits PCa development and metastasis. We extended these studies and more recently observed increased expression of genes related to angiogenesis such as vascular endothelial growth factor (VEGF) and those related to metastasis such as matrix metalloproteinases (MMP)-2 and MMP-9 in prostate cancer of TRAMP mice. Oral feeding of GTP as the sole source of drinking fluid to TRAMP mice results in significant inhibition of VEGF, MMP-2 and MMP-9. These data suggest that there are multiple targets for PCa chemoprevention by green tea and highlight the need for further studies to identify novel pathways that may be modulated by green tea or its polyphenolic constituents that could be further exploited for prevention and/or treatment of PCa.
前列腺癌（PCa）是美国男性中最常被诊断出的恶性肿瘤，也是癌症相关死亡的第二大原因。基于这些原因，有必要加大力度，以更好地理解并开发针对这种疾病的新型治疗方法和化学预防方法。近年来，绿茶作为一种可能降低多种癌症风险的物质，受到了广泛关注。绿茶的癌症化学预防作用似乎是由其中所含的多酚成分介导的。基于地理观察结果表明，经常饮用绿茶的日本和中国人群中PCa的发病率较低，我们推测绿茶及其成分可能对PCa的化学预防有效。为了验证这一假设，我们启动了一项用绿茶进行PCa化学预防的计划。在使用人PCa细胞DU145（雄激素不敏感）和LNCaP（雄激素敏感）的细胞培养系统中，我们发现绿茶的主要多酚成分（-）-表没食子儿茶素-3-没食子酸酯（EGCG）可诱导：1）细胞凋亡；2）细胞生长抑制；3）细胞周期蛋白激酶抑制剂WAF-1/p21介导的细胞周期失调。最近，通过cDNA微阵列，我们发现用EGCG处理LNCaP细胞会导致：1）诱导功能上表现出生长抑制作用的基因；2）抑制属于G蛋白信号网络的基因。在使用小鼠前列腺转基因腺癌（TRAMP）的动物研究中，TRAMP是一种模拟人类前列腺疾病进展形式的模型，我们观察到以人类可达到的剂量（相当于每天6杯绿茶）口服从绿茶中分离出的多酚组分（GTP）可显著抑制PCa的发展和转移。我们扩展了这些研究，最近观察到TRAMP小鼠前列腺癌中与血管生成相关的基因如血管内皮生长因子（VEGF）以及与转移相关的基因如基质金属蛋白酶（MMP）-2和MMP-9的表达增加。将GTP作为唯一的饮用水源口服给TRAMP小鼠可显著抑制VEGF、MMP-2和MMP-9。这些数据表明，绿茶对PCa化学预防有多个靶点，并强调需要进一步研究以确定可能由绿茶或其多酚成分调节的新途径，这些途径可进一步用于PCa的预防和/或治疗。
