Induction of apoptosis in human leukemia cells by 3-deazaadenosine is mediated by caspase-3-like activity.
3-Deazaadenosine (DZA), one of the potent inhibitors of S-adenosylhomocysteine hydrolase, is known to possess several biological properties including an induction of apoptosis. To evaluate a possibility that DZA may be utilized for the treatment of human leukemia, we studied molecular events of cell death induced by DZA in human leukemia HL-60 and U-937 cells. DZA induced a specific cleavage of poly ADP-ribose polymerase (PARP) and an activation of the cysteine protease caspase-3/CPP32 which is known to cleave PARP. DZA-mediated nuclear DNA-fragmentation was completely blocked in the presence of a universal inhibitor of caspases (z-VAD-fmk) or the specific inhibitor of caspase-3 (z-DEVD-fmk) unlike of cycloheximide (CHX). DNA fragmentation was preceded by the lowering of c-myc mRNA in the DZA treated cells. In addition, DZA-induced apoptosis was blocked by pretreatment with adenosine transporter inhibitors such as nitrobenzylthioinosine (NBTI) and dipyridamole (DPD). Taken together, these results demonstrate that DZA-induced apoptosis initiated through an active transport of DZA into human leukemia cells, is dependent on the caspase-3-like activity without de novo synthesis of proteins and possibly involves c-myc down-regulation.
Kim
H S
HS
Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul.
Jeong
S Y
SY
Lee
J H
JH
Kim
B E
BE
Kim
J W
JW
Jeong
S W
SW
Kim
I K
IK
D000241:Adenosine / Q000378:metabolism; D017209:Apoptosis; D001693:Biological Transport, Active; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation; D016259:Genes, myc; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D014372:Tubercidin / Q000494:pharmacology*; D020298:U937 Cells
D002352:Carrier Proteins; D014157:Transcription Factors; C018258:3-deazaadenosine; D013868:Thioinosine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C001789:4-nitrobenzylthioinosine; D000241:Adenosine; D014372:Tubercidin