Abstract 4091: The oral iron chelator, deferasirox, induces apoptosis in myeloid leukemia cells through caspase-dependent activation

Abstract

Abstract Iron plays a central role in the regulation of many cellular function. Recently several studies suggest that iron chelator, deferoxamine acts as an anti-cancer drug on various cancers. deferasirox(DFS) is a new oral iron chelator. Some of the papers has recently been reported that effect antiproliferative on leukemia cell by DFS but the effects of DFS on myeloid leukemia cells have not been clearly elucidated. We measured the sensitivity of human leukemic cell lines (HL-60 and KG-1) to DFS using MTT assay. The proliferation of cells treated with DFS at various concentrations for various time was decreased in a dose-and time-dependent manner. Cell cycle analysis for subG1 fraction also detected the increased cell death in the cells treated with DFS. To determine whether DFS-mediated cell death was due to apoptosis in HL-60 and KG-1 cell lines, percentages of apoptotic cell were measured by staining with FITC-conjugated annexin V and PI. The percentage of apoptotic cells was significantly increased by DFS stimulation. Results by Western blotting and colorimetric assay indicated that DFS promotes apoptosis of human leukemic cells by both activating caspase-3 and -9 and inducing PARP cleavage. Furthermore, pretreated of leukemic cells with caspase inhibitor (z-V) significantly inhibited the DFS-induced apoptosis. In the in vivo model, treatment of leukemic tumor-bearing athymic nude mouse with DFS was showed significant decrease in tumor growth compared with treatment with DMSO. These results demonstrate that a new oral iron-chelating agent, DFS, promotes apoptosis of myeloid leukemia cells via activating caspase 3/9, suggesting that DFS might be beneficial for iron-overloaded patients with myeloid leukemia, not only from iron chelation but also from reduction of leukemia cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4091. doi:10.1158/1538-7445.AM2011-4091