Reactive oxygen intermediate(s) (ROI): common mediator(s) of poly(ADP-ribose)polymerase (PARP) cleavage and apoptosis.
HL-60 acute myeloblastic and U937 monoblastoid leukaemic cell lines both cleave poly(ADP-ribose)polymerase (PARP), at the onset of apoptosis, in response to a wide range of cytotoxic agents. This appears to be a common feature of leukaemic cell apoptosis. However, in the chronic myelogenous leukaemic (CML) derived cell line, K562, no such cleavage was detectable. This correlated with previous findings that this cell line is particularly resistant to apoptosis induced by cytotoxic agents. Proteolytic cleavage of PARP and the subsequent progression to apoptosis was inhibited by two protease inhibitors NEM and IOD. As both PARP cleavage and DNA fragmentation appeared closely linked in these cell lines, anti-oxidants (previously shown to be effective inhibitors of DNA fragmentation and apoptosis) were also demonstrated to prevent PARP cleavage. These results combine to suggest that ROI may mediate PARP cleavage, DNA fragmentation and the eventual apoptosis of these cells following cytotoxic insult.
McGowan
A J
AJ
Tumour Biology Laboratory, Department of Biochemistry, University College Cork, Ireland.
Ruiz-Ruiz
M C
MC
Gorman
A M
AM
Lopez-Rivas
A
A
Cotter
T G
TG
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D015853:Cysteine Proteinase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; D003546:Cysteine Endopeptidases