Inhibition of epidermal growth factor-induced cell transformation by tannins

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 E6-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. (c) 2005 Elsevier Ltd. All rights reserved.