Molecular targets for green tea in prostate cancer prevention
Molecular targets for green tea in prostate cancer prevention
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DOI：
10.1093/jn/133.7.2417s
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发表时间：
2003-07-01
影响因子：
4.2
通讯作者：
Mukhtar, H
中科院分区：
文献类型：
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作者：
Adhami, VM;Ahmad, N;Mukhtar, H
前列腺癌（PCa）是最常见的恶性肿瘤，也是美国男性癌症相关死亡的第二大原因。由于这些原因，有必要加强我们的努力，以更好地了解和发展新的治疗和化学预防方法。近年来，绿茶作为一种可以降低几种癌症风险的物质而受到了相当大的关注。绿茶的癌症化学预防作用似乎是由其中的多酚成分介导的。根据地理观察表明，在经常饮用绿茶的日本和中国人群中，前列腺癌的发病率较低，我们假设绿茶和/或其成分可能对前列腺癌的化学预防有效。为了研究这一假设，我们发起了一项绿茶化学预防前列腺癌的计划。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）诱导1）细胞凋亡，2)细胞生长抑制和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，利用cDNA微阵列，我们发现EGCG处理LNCaP细胞导致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。在动物研究中，采用转基因小鼠前列腺腺癌（TRAMP），这是一种模拟人类前列腺疾病进行性形式的模型，我们观察到，以人类可达到的剂量（相当于6杯绿茶/d）口服绿茶（GTP）中分离的多酚部分，可显著抑制前列腺癌的发展和转移。我们扩展了这些研究，最近观察到与血管生成相关的基因，如血管内皮生长因子（VEGF）和与转移相关的基因，如基质金属蛋白酶(MMP)-2和MMP-9在TRAMP小鼠前列腺癌中的表达增加。口服GTP作为唯一的饮水来源，对TRAMP小鼠的VEGF、MMP-2和MMP-9有明显的抑制作用。这些数据表明，绿茶有多种化学预防前列腺癌的靶点，并强调需要进一步研究确定绿茶或其多酚成分可能调节的新途径，从而进一步开发预防和/或治疗前列腺癌的方法。
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.