dithizone and benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone

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.

Topics: Amino Acid Chloromethyl Ketones; Apoptosis; Caspase 3; Caspase 9; Caspase Inhibitors; Caspases; Cell Differentiation; Chelating Agents; Cysteine Proteinase Inhibitors; Dithizone; Drug Interactions; Drug Resistance, Neoplasm; Enzyme Activation; Intracellular Membranes; Leukemia, Promyelocytic, Acute; Macrophage-1 Antigen; Membrane Potentials; Mitochondria; Neoplasm Proteins; Neoplastic Stem Cells; Oncogene Proteins, Fusion; Signal Transduction; Tretinoin; Tumor Cells, Cultured