Growth inhibitory effect of green tea extract and (-)-epigallocatechin in Ehrlich ascites tumor cells involves a cellular thiol-dependent activation of mitogenic-activated protein kinases

The effect of green tea extract (GTE) in Ehrlich ascites tumor cells (EATC) was studied with respect to changes in the intracellular kinase system inv olving mitogen-activated protein kinases (MAPKs) and cellular thiol. We hav e previously shown a reduction in viability of EATC and tyrosine phosphoryl ation of 42 and 45 kDa proteins by GTE and its polyphenolic component, Epig allocatechin (EGC) (D.O. Kennedy, S. Nishimura, T. Hasuma. Y. Yoshihisa, S. Otani, I. Matsui-Yuasa, Involvement of protein tyrosine phosphorylation in the effect of green tea polyphenols on Ehrlich ascites turner cells in vit ro, Chem. Biol. Interact. 110 (1998) 159-172). Furthermore, GTE and EGC sig nificantly decreased both cellular non-protein and protein sulfhydryl level s in EATC, but replenishing thiol stores with N-acetylcysteine (NAC) caused a recovery in cell viability, and therefore SH groups were identified as a novel target of green tea cytotoxicity (D.O. Kennedy, M. Matsumoto. A. Koj ima. I. Matsui-Yuasa. Cellular thiol status and cell death in the effect of green tea polyphenols in Ehrlich ascites tumor cells, Chem. Biol. Interact . 122 (1999) 59-71). In this study, we have observed the stimulation of thr ee forms of MAPK, namely ERK1/2, JNK/SAPK and p38, by EGG, which were dose and time-dependent. These MAPK stimulations were found to be cellular thiol status-dependent events as: NAC reversed these stimulations. Furthermore, inhibition of the p38 MAPK pathway using the p38 inhibitor SB203580 caused a marked dose-dependent reduction in the decrease in cell viability caused by EGC treatment. Inhibiting the Erk1/2 MAPK pathway using the MEK inhibito r PD098059 caused a slight change in the decrease in cell viability by EGG. These may suggest that the cytotoxicity associated with EGC was more assoc iated with the other MAPKs: than with ERK1/2. This may be the first study o f its kind providing a novel evidence of a role for different forms of MAPK s in the antitumoric effect of green tea polyphenols, especially EGG, in Eh rlich ascites tumor cells. (C) 2001 Elsevier Science Ireland Ltd. All right s reserved.