Masuda Muneyuki, Suzui Masumi, Lim Jin T E, Weinstein I Bernard
Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Clin Cancer Res. 2003 Aug 15;9(9):3486-91.
Overexpression of the HER-2/neu receptor (HER-2) is associated with a poor prognosis in patients with breast carcinoma and also in patients with head and neck squamous cell carcinoma (HNSCC). In a previous study on HNSCC cell lines, we found that epigalocathechin-3-gallate (EGCG), a major biologically active component of green tea, inhibited activation of the epidermal growth factor receptor (EGFR) and thereby inhibited EGFR-related downstream signaling pathways in HNSCC cells. In the present study, we examined the effects of EGCG on activation of the HER-2 receptor in human HNSCC and breast carcinoma cell lines that display constitutive activation of HER-2. Treatment of these cells with 10 or 30 microg of EGCG, respectively, doses that cause 50% inhibition of growth, markedly inhibited the phosphorylation of HER-2 in both cell lines. This was associated with inhibition of Stat3 activation, inhibition of c-fos and cyclin D1 promoter activity, and decreased cellular levels of the cyclin D1 and Bcl-XL proteins. Although these concentrations of EGCG are quite high, we found that concentrations of 0.1-1.0 microg/ml, which are in the range of plasma concentrations after administering a single oral dose of EGCG or a green tea extract, markedly enhanced the sensitivity of both types of cell lines to growth inhibition by Taxol, a drug frequently used in the treatment of breast carcinoma and HNSCC. These results, taken together with previous evidence that EGCG also inhibits activation of the EGFR in carcinoma cells, suggest that EGCG may be useful in treating cases of breast carcinoma and HNSCC in which activation of the EGFR and/or HER-2 plays important roles in tumor survival and growth.
HER-2/neu受体（HER-2）的过表达与乳腺癌患者以及头颈部鳞状细胞癌（HNSCC）患者的不良预后相关。在之前一项关于HNSCC细胞系的研究中，我们发现表没食子儿茶素-3-没食子酸酯（EGCG），绿茶的一种主要生物活性成分，可抑制表皮生长因子受体（EGFR）的激活，从而抑制HNSCC细胞中与EGFR相关的下游信号通路。在本研究中，我们检测了EGCG对人HNSCC和乳腺癌细胞系中HER-2受体激活的影响，这些细胞系表现出HER-2的组成性激活。分别用10或30微克EGCG处理这些细胞，这两种剂量可导致50%的生长抑制，显著抑制了两种细胞系中HER-2的磷酸化。这与Stat3激活的抑制、c-fos和细胞周期蛋白D1启动子活性的抑制以及细胞周期蛋白D1和Bcl-XL蛋白细胞水平的降低有关。尽管这些EGCG浓度相当高，但我们发现0.1 - 1.0微克/毫升的浓度，处于单次口服EGCG或绿茶提取物后血浆浓度范围内，显著增强了这两种细胞系对紫杉醇生长抑制的敏感性，紫杉醇是一种常用于治疗乳腺癌和HNSCC的药物。这些结果，连同之前关于EGCG也抑制癌细胞中EGFR激活的证据，表明EGCG可能有助于治疗EGFR和/或HER-2激活在肿瘤存活和生长中起重要作用的乳腺癌和HNSCC病例。
