Antitumor activity and mechanism of action of the iron chelator, Dp44mT, against leukemic cells.
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.
Noulsri
Egarit
E
Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Richardson
Des R
DR
Lerdwana
Surada
S
Fucharoen
Suthat
S
Yamagishi
Tetsuo
T
Kalinowski
Danuta S
DS
Pattanapanyasat
Kovit
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D009101:Multiple Myeloma / Q000188:drug therapy*; D013882:Thiosemicarbazones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007502:Iron Chelating Agents; D013882:Thiosemicarbazones; C539263:di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone