Induction of apoptosis in human leukemia cells by 3-deazaadenosine is mediated by caspase-3-like activity.
- Author:
Ho Shik KIM
1
;
Seong Yun JEONG
;
Jeong Hwa LEE
;
Boe Eun KIM
;
Jin Woo KIM
;
Seong Whan JEONG
;
In Kyung KIM
Author Information
1. Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul.
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
3-deazaadenosine;
leukemia;
apoptosis;
caspase;
c-myc
- MeSH:
Adenosine/metabolism;
*Apoptosis;
Biological Transport, Active;
Carrier Proteins/metabolism;
Caspases/*metabolism;
Down-Regulation;
Enzyme Activation;
Genes, myc;
HL-60 Cells;
Human;
Leukemia, Promyelocytic, Acute/*drug therapy;
Thioinosine/*analogs & derivatives/pharmacology;
Transcription Factors/genetics;
Tubercidin/*pharmacology;
U937 Cells
- From:Experimental & Molecular Medicine
2000;32(4):197-203
- CountryRepublic of Korea
- Language:English
-
Abstract:
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.
