Iron chelators have been reported to induce apoptosis and cell cycle arrest in
cancer cells. Recent studies suggest broad and selective antitumor activity of the new
iron chelator,
di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (
Dp44mT; Whitnall et al., Proc Natl Acad Sci USA 2006;103:14901-14906). However, little is known concerning its effects on
hematological malignancies. Using acute
leukemia cells, the effect of
Dp44mT on apoptosis, cell cycle,
caspase-3 activation, and mitochondrial trans-membrane potential has been examined by flow cytometry.
Dp44mT acted to induce a G(1)/S arrest in NB4 promyelocytic
leukemia cells at low concentrations (0.5-2.5 microM), being far more effective than the clinically used
chelator,
desferrioxamine (DFO). Moreover,
Dp44mT induced apoptosis of NB4 cells in a dose- and time-dependent manner with markedly less effect on nonproliferating cells. The apoptosis-inducing activity of
Dp44mT was significantly more effective than DFO. Furthermore, this study also showed that
Dp44mT had broad activity, inducing apoptosis in several types of acute
leukemia and also
multiple myeloma cell lines. Additional studies examining the cytotoxic mechanisms of
Dp44mT showed that a reduction in the mitochondrial trans-membrane potential and
caspase-3 activation could be involved in the mechanism of apoptosis. Our results suggest that
Dp44mT possesses potential as an effective
cytotoxic agent for the chemotherapeutic treatment of acute
leukemia.