title: 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.
abstract: 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: Division of Hematology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors: Chiharu
authors: C
authors: Kawamura
authors: Masahiro
authors: M
authors: Kizaki
authors: Yumi
authors: Y
authors: Fukuchi
authors: Yasuo
authors: Y
authors: Ikeda
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004230:Dithizone / Q000494:pharmacology*; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D007425:Intracellular Membranes / Q000187:drug effects; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D002614:Chelating Agents; D015853:Cysteine Proteinase Inhibitors; D016177:Macrophage-1 Antigen; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D004230:Dithizone; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases