The cytotoxicity of arsenic trioxide to normal hematopoietic progenitors and leukemic cells is dependent on their cell-cycle status.
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 (< or = 5 microM) caused prolongation of G1/S and G2/M phase in a dose-dependent manner. The percentage of cells in G2/M increased significantly (from 8.6 to 53.8%). High-dose ATO (> or = 25 microM) 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 G0/G1 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.
Huang
Ming-Jer
MJ
Department of Hemato-oncology, Taipei Mackay Memorial Hospital, Taipei, Taiwan.
Hsieh
Ruey-Kuen
RK
Lin
Che-Pin
CP
Chang
Ian Y
IY
Liu
Hsing-Jin
HJ
D018952:Antigens, CD34; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004351:Drug Resistance; D005434:Flow Cytometry; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D016130:Immunophenotyping; D007399:Interphase / Q000187:drug effects; D007938:Leukemia / Q000473:pathology*; D010087:Oxides / Q000494:pharmacology*
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D000077237:Arsenic Trioxide