The Cytotoxicity of Arsenic Trioxide to Normal Hematopoietic Progenitors and Leukemic Cells is Dependent on Their Cell-cycle Status

Abstract

Arsenic trioxide (ATO) is a novel agent to treat acute promyelocytic leukemia (APL). ATO can degrade chimeric PML-RAR proteins and induce apoptosis in various cancer cells. However, its effects on primary hematopoietic CD34 + have not been examined. In this study, we compared the effects of ATO on HL60 leukemic cells and primary umbilical cord blood (UCB) CD34 + cells. HL60 cells and UCB CD34 + cells were cultured with different concentrations of ATO for up to three weeks and examined for changes of cell cycle. We found that ATO (≤ 5 µ M) caused prolongation of G 1 /S and G 2 /M phase in a dose-dependent manner. The percentage of cells in G 2 /M increased significantly (from 8.6 to 53.8%). High-dose ATO (≥ 25 µ M) caused non-specific cell death in HL60 cells without any changes in cell cycle. In contrast to HL60 cells, UCB CD34 + cells were more resistant to high-dose ATO and most ATO-resistant CD34 + cells remained in G 0 /G 1 phase. Primary cells that were resistant to ATO were rich in CD34 + cells. We further show that the ATO resistance was not related to the expression of P-glycoprotein (MDR-1). Our results suggest that the resistance to ATO in primitive UCB CD34 + cells is most likely related to its cell-cycle status. These results could be useful to design treatments for non-APL malignancies and to enrich hematopoietic stem cells in clinically applicable settings.