Nomura Masaaki, Tsukada Hirotaka, Ichimatsu Daisuke, Ito Hideyuki, Yoshida Takashi, Miyamoto Ken-Ichi
Department of Hospital Pharmacy, School of Medicine, Kanazawa University, 13-1 Takara-Machi, Kanazawa, Ishikawa 920-8641, Japan.
Phytochemistry. 2005 Sep;66(17):2038-46. doi: 10.1016/j.phytochem.2005.01.018.
The mouse epidermal JB6 cell system is a well developed model for studying tumor promotion, and the JB6 Cl 41 promotion sensitive (P+) cell line, in which transformed colonies are induced by epidermal growth factor (EGF), was used to test the anti-tumor promoting effect of seven tannins and two triterpenoids. We found that six tannins, ellagitannins (compounds 1, 2, 3 and 4) and chromone gallates (compounds 6 and 7), significantly blocked EGF-induced cell transformation in a concentration-dependent manner. The inhibition of cell transformation by the tannins was not due to growth inhibition. The ellagitannins, but not the chromone gallates, significantly attenuated EGF-induced activator protein 1 (AP-1) activation, a transcription factor. Compounds 1 and 3, among the ellagitannins analysed, inhibited the EGF-induced phosphorylation of extracellular-signal regulated protein kinases and p38 kinases, which regulate AP-1 activation. On the other hand, compounds 3 and 4 suppressed EGF-induced phosphatidylinositol 3-kinase (PI3K) activation. In addition, all tannins that blocked cell transformation markedly inhibited EGF-induced activation of Akt, a downstream effector of PI3K. Because signal-transduction pathways, including AP-1 and PI3K pathways, have been focused as prime targets for chemopreventive phytochemicals, our results suggest that inhibition by tannins of EGF-induced neoplastic transformation in JB6 cells is related to blocking of Akt activation, and also attenuation of AP-1 activation for ellagitannins.
小鼠表皮JB6细胞系统是研究肿瘤促进作用的一个成熟模型，其中表皮生长因子（EGF）诱导转化集落形成的JB6 Cl 41促进敏感（P+）细胞系被用于测试7种单宁和2种三萜类化合物的抗肿瘤促进作用。我们发现，6种单宁，即鞣花单宁（化合物1、2、3和4）和色酮没食子酸盐（化合物6和7），以浓度依赖性方式显著阻断EGF诱导的细胞转化。单宁对细胞转化的抑制作用并非由于生长抑制。鞣花单宁而非色酮没食子酸盐，显著减弱了EGF诱导的转录因子激活蛋白1（AP-1）的激活。在所分析的鞣花单宁中，化合物1和3抑制了EGF诱导的细胞外信号调节蛋白激酶和p38激酶的磷酸化，这两种激酶调节AP-1的激活。另一方面，化合物3和4抑制了EGF诱导的磷脂酰肌醇3-激酶（PI3K）的激活。此外，所有阻断细胞转化的单宁均显著抑制了EGF诱导的PI3K下游效应器Akt的激活。由于包括AP-1和PI3K途径在内的信号转导途径已成为化学预防植物化学物质的主要作用靶点，我们的结果表明，单宁对JB6细胞中EGF诱导的肿瘤转化的抑制作用与阻断Akt激活有关，对于鞣花单宁还与减弱AP-1激活有关。
