Abstract
Arsenic trioxide exhibits therapeutic effects on certain blood malignancies, at least partly by modulating cell differentiation. Previous in vitro studies in human hematopoietic progenitor cells have suggested that arsenic may inhibit erythroid differentiation. However, these effects were all observed in the presence of arsenic compounds, while the concomitant cytostatic and cytotoxic actions of arsenic might mask a prodifferentiating activity. To eliminate the potential impacts of the cytostatic and cytotoxic actions of arsenic, we adopted a novel protocol by pretreating human bone marrow CD34+ cells with a low, noncytotoxic concentration of arsenic trioxide, followed by assaying the colony forming activities in the absence of the arsenic compound. Bone marrow specimens were obtained from chronic myeloid leukemia patients who achieved complete cytogenetic remission. CD34+ cells were isolated by magnetic-activated cell sorting. We discovered that arsenic trioxide enhanced the erythroid colony forming activity, which was accompanied by a decrease in the granulomonocytic differentiation function. Moreover, in erythroleukemic K562 cells, we showed that arsenic trioxide inhibited erythrocyte maturation, suggesting that arsenic might have biphasic effects on erythropoiesis. In conclusion, our data provided the first evidence showing that arsenic trioxide could prime human hematopoietic progenitor cells for enhanced erythroid differentiation.
Highlights
Inorganic arsenic, mainly in the form of arsenic trioxide (ATO), has been proved to be effective in the treatment of certain blood malignancies [1, 2]
We screened the effects of ATO of different concentrations on CD34+ bone marrow (BM) cell viability
Following a 7-day treatment period, ATO at 0.5 μM showed no effects on cell apoptosis or necrosis, while ATO at 2 and 5 μM increased the proportion of cells in the necrotic and late apoptotic status by 3-4-fold (Figure 1(b))
Summary
Mainly in the form of arsenic trioxide (ATO), has been proved to be effective in the treatment of certain blood malignancies [1, 2]. Induction of differentiation and apoptosis of leukemic cells may have an essential role in the therapeutic action of ATO [3]. Previous in vitro studies in human hematopoietic progenitor cells have suggested that arsenic may inhibit erythroid differentiation [5, 6]. These effects were all observed in the presence of arsenic throughout the process of differentiation induction. Since ATO has cytostatic and cytotoxic actions in human hematopoietic cells [5, 6], these effects may potentially influence the results of the subsequent differentiation assay
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