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Antitumor activity and mechanism of action of the iron chelator, Dp44mT, against leukemic cells
Author(s) -
Noulsri Egarit,
Richardson Des R.,
Lerdwana Surada,
Fucharoen Suthat,
Yamagishi Tetsuo,
Kalinowski Danuta S.,
Pattanapanyasat Kovit
Publication year - 2009
Publication title -
american journal of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.456
H-Index - 105
eISSN - 1096-8652
pISSN - 0361-8609
DOI - 10.1002/ajh.21350
Subject(s) - apoptosis , cytotoxic t cell , acute promyelocytic leukemia , leukemia , cancer research , cell cycle , flow cytometry , cancer cell , mechanism of action , chemistry , cell culture , pharmacology , biology , immunology , cancer , medicine , biochemistry , in vitro , retinoic acid , genetics
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 G 1 /S arrest in NB4 promyelocytic leukemia cells at low concentrations (0.5–2.5 μM), 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. Am. J. Hematol. 2009. © 2008 Wiley‐Liss, Inc.