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.
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Authors | H S Kim, S Y Jeong, J H Lee, B E Kim, J W Kim, S W Jeong, I K Kim |
Journal | Experimental & molecular medicine
(Exp Mol Med)
Vol. 32
Issue 4
Pg. 197-203
(Dec 31 2000)
ISSN: 1226-3613 [Print] United States |
PMID | 11190270
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Carrier Proteins
- Transcription Factors
- 3-deazaadenosine
- Thioinosine
- CASP3 protein, human
- Caspase 3
- Caspases
- 4-nitrobenzylthioinosine
- Adenosine
- Tubercidin
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Topics |
- Adenosine
(metabolism)
- Apoptosis
- Biological Transport, Active
- Carrier Proteins
(metabolism)
- Caspase 3
- Caspases
(metabolism)
- Down-Regulation
- Enzyme Activation
- Genes, myc
- HL-60 Cells
- Humans
- Leukemia, Promyelocytic, Acute
(drug therapy)
- Thioinosine
(analogs & derivatives, pharmacology)
- Transcription Factors
(genetics)
- Tubercidin
(pharmacology)
- U937 Cells
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