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 lymphocytic leukaemia (CLL) cells by fludarabine. However, it is unclear whether these enzymes are required for the induction of such killing, or whether they simply determine the mode of cell death. To address this question, we examined 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-ribose) polymerase (PARP) cleavage and DNA fragmentation, other manifestations of cell death (mitochondrial depolarization, exposure of phosphatidyl serine, cell membrane disruption and cell shrinkage) are caspase independent. By showing that caspases influence the mode, but not the extent, of nucleoside cytotoxicity, our results exclude defects in these enzymes as a mechanism of nucleoside resistance in CLL.
Department of Haematology, University of Liverpool, Liverpool, UK.
A R
AR
Pettitt
J C
JC
Cawley
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology*; D002462:Cell Membrane / Q000473:pathology; D048429:Cell Size; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology / Q000503:physiopathology*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020169:Caspases; D014740:Vidarabine; C024352:fludarabine