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Title: Antitumor activity and mechanism of action of the iron chelator, Dp44mT, against leukemic cells
Authors: Egarit Noulsri
Des R. Richardson
Surada Lerdwana
Suthat Fucharoen
Tetsuo Yamagishi
Danuta S. Kalinowski
Kovit Pattanapanyasat
Mahidol University
The University of Sydney
The Institute of Science and Technology for Research and Development, Mahidol University
Keywords: Medicine
Issue Date: 1-Mar-2009
Citation: American Journal of Hematology. Vol.84, No.3 (2009), 170-176
Abstract: 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 G1/S arrest in NB4 promyelocytic leukemia cells at low concentrations (0.5-2.5 μM), being far more effective than the clinically used chelator, desferoxamine (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 transmembrane 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. © 2008 Wiley-Liss, Inc.
ISSN: 10968652
Appears in Collections:Scopus 2006-2010

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