Document Detail


A metal chelator, diphenylthiocarbazone, induces apoptosis in acute promyelocytic leukemia (APL) cells mediated by a caspase-dependent pathway without a modulation of retinoic acid signaling pathways.
MedLine Citation:
PMID:  12008084     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A metal chelator, diphenylthiocarbazone (dithizone), has been reported to induce differentiation and apoptosis of the human myeloid leukemia cell line HL-60, however, very little is known about the mechanism of dithizone-induced apoptosis. Here, we report for the first time that dithizone can induce inhibition of cellular growth of retinoic acid (RA)-sensitive NB4 and RA-resistant UF-1 APL cells via induction of apoptosis but not differentiation. Treatment of NB4 cells with dithizone markedly-induced apoptosis, which was associated with the loss of mitochondrial transmembrane potentials (Delta Psi(m)) and activation of caspase-3 and -9. Further investigation of the RA-resistant UF-1 APL cells showed that dithizone-induced apoptosis to a lesser extent. However, neither dithizone alone nor in combination with all-trans RA induced the expression of myeloid differentiation antigen CD11b. Concomitantly, the degradation of PML/RARalpha fusion protein was not observed after treatment with dithizone alone, and the degradation was not enhanced by the combination of dithizone and all-trans RA. We conclude that dithizone, a metal chelator, induced apoptosis without differentiation in APL cells in association with Delta Psi(m) collapse and caspase-3 and -9 activation.
Authors:
Chiharu Kawamura; Masahiro Kizaki; Yumi Fukuchi; Yasuo Ikeda
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Leukemia research     Volume:  26     ISSN:  0145-2126     ISO Abbreviation:  Leuk. Res.     Publication Date:  2002 Jul 
Date Detail:
Created Date:  2002-05-14     Completed Date:  2002-08-08     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7706787     Medline TA:  Leuk Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  661-8     Citation Subset:  IM    
Affiliation:
Division of Hematology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Chloromethyl Ketones / pharmacology
Apoptosis / drug effects*
Caspase 3
Caspase 9
Caspases / antagonists & inhibitors,  physiology*
Cell Differentiation / drug effects
Chelating Agents / pharmacology*
Cysteine Proteinase Inhibitors / pharmacology
Dithizone / pharmacology*
Drug Interactions
Drug Resistance, Neoplasm
Enzyme Activation / drug effects
Intracellular Membranes / drug effects
Leukemia, Promyelocytic, Acute / pathology*
Macrophage-1 Antigen / biosynthesis
Membrane Potentials / drug effects
Mitochondria / drug effects
Neoplasm Proteins / antagonists & inhibitors,  physiology*
Neoplastic Stem Cells / cytology,  drug effects*,  enzymology
Oncogene Proteins, Fusion / physiology
Signal Transduction / drug effects*
Tretinoin / pharmacology*
Tumor Cells, Cultured / cytology,  drug effects,  enzymology
Chemical
Reg. No./Substance:
0/Amino Acid Chloromethyl Ketones; 0/Chelating Agents; 0/Cysteine Proteinase Inhibitors; 0/Macrophage-1 Antigen; 0/Neoplasm Proteins; 0/Oncogene Proteins, Fusion; 0/benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; 0/promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; 302-79-4/Tretinoin; 60-10-6/Dithizone; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/CASP9 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 9; EC 3.4.22.-/Caspases

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