EXPRESSION OF APOPTOSIS-RELATED ONCOPROTEINS AND MODULATION OF APOPTOSIS BY CAFFEINE IN HUMAN LEUKEMIC-CELLS

We investigated the modulation of radio- and chemoresistance by caffei ne and mechanisms of resistance in human leukemic cell lines and monon uclear cells from 18 leukemic patients. Caffeine synergistically poten tiated cytotoxicity and apoptosis induced by ionizing radiation or car boplatin (CPt), but attenuated induction of apoptosis by daunorubicin (DNR) in KG-1a cells. Since caffeine released irradiated as well as DN R-treated KG-1a cells from G(2)M cell cycle arrest and CPt-treated cel ls from S-phase arrest, this release does not fully explain the differ ent effects of caffeine. Caffeine synergistically reduced the level of the apoptosis inhibitor glutathione after irradiation or CPt treatmen t. In contrast, treatment with DNR plus caffeine diminished glutathion e levels to a lesser extent than DNR alone. We conclude that the effec t of caffeine on glutathione depletion represents a mechanism of actio n by which caffeine can modulate apoptosis. Caffeine increased CPt cyt otoxicity in K562 cells and its doxorubicin-resistant subline (K562/AD M), but little effect was seen in HL-60 cells or mononuclear cells fro m leukemic patients. Multivariate cluster analysis revealed an associa tion of CPt resistance with the expression of c-Fos, c-N-Ras, and p53 oncoproteins and with proliferative activity (S-phase of cell cycle), but not with Bcl-2 expression.