Abstract
Glucocorticoids and fludarabine are able to induce typical features of apoptosis in CLL lymphocytes. Cysteinyl aspartate specific proteases (caspases) play a key biochemical role in the apoptotic pathway. Caspase activation following cytotoxic stimuli leads to highly specific proteolytic cleavage of functionally important cellular enzymes. One of them is poly ADP-ribose) polymerase (PARP). To some extent caspase activation seems to be under the control of the Bcl-2 family of interacting proteins. We determined the role of Bcl-2-family proteins Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic), activation of caspase-3 (CPP32/Yama) and activation of PARP in CLL apoptosis. All 21 analyzed CLL samples expressed Bcl-2 and Bax. Four of 13 (31%) samples with a low Bcl-2/Bax ratio exhibited in vitro prednisolone resistance, whereas eight of nine (88%) samples with a high Bcl-2/Bax ratio were in vitro resistant (</=0.025). There was no significant correlation between clinical pre-treatment status and Bcl-2/Bax ratio. Caspase-3/CPP32 activity increase was registered after dexamethasone as well as after fludarabine treatment in CLL lymphocytes in vitro. Caspase inhibitor Z-VAD.fmk was only able to partially block dexamethasone-induced and spontaneous apoptosis but not fludarabine-induced apoptosis in CLL lymphocytes. PARP activity decreased after dexamethasone and fludarabine treatment. PARP inhibitor 3-aminobenzamide (3-AB) was able to partially inhibit dexamethasone-induced apoptosis but not fludarabine-induced and spontaneous apoptosis.
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