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 (Δ Ψ 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/RARα 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 Δ Ψ m collapse and caspase-3 and -9 activation.