Caspases influence the mode but not the extent of cell death induced by purine analogues in chronic lymphocytic leukaemia

Caspases are known to be involved in the apoptotic killing of chronic lymph ocytic leukaemia (CLL) cells by fludarabine. However, it is unclear whether these enzymes are required for the induction of such killing, or whether t hey simply determine the mode of cell death. To address this question, we e xamined the effect of the broad-spectrum caspase inhibitor Z-VAD.fmk on six different manifestations of nucleoside cytotoxicity. Our results indicate that while caspase activity is required for nucleoside-induced poly(ADP-rib ose) polymerase (PARP) cleavage and DNA fragmentation, other manifestations of cell death (mitochondrial depolarization, exposure of phosphatidyl seri ne, cell membrane disruption and cell shrinkage) are caspase independent. B y showing that caspases influence the mode, but not the extent, of nucleosi de cytotoxicity, our results exclude defects in these enzymes as a mechanis m of nucleoside resistance in CLL.