Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL) : I. As2O3 exerts dose-dependent dual effects on APL cells

Recent clinical studies in China showed that As 2 O 3 is an effective and relatively safe drug in the treatment of acute promyelocytic leukemia (APL). We found previously that As 2 O 3 can trigger apoptosis of APL cell line NB4 cells, which is associated with downregulation of bcl-2 gene expression and modulation of PML-RARα chimeric protein. To further understand the mechanisms of this alternative therapy for APL, we investigated in this report the effects of a wide range of concentrations of As 2 O 3 on cultured primary APL cells, all-trans retinoic acid (ATRA)-susceptible (NB4 cells) and ATRA-resistant (MR2 subclone) APL cell lines. The results indicated that As 2 O 3 had dose-dependent dual effects on APL cells: inducing preferentially apoptosis at relatively high concentrations (0.5 to 2 μmol/L) and inducing partial differentiation at low concentrations (0.1 to 0.5 μmol/L). The rapid modulation and degradation of PML-RARα proteins, which was induced by As 2 O 3 at 0.1 to 2 μmol/L, could contribute to these two effects. Bone marrow and peripheral blood examination showed that myelocyte-like cells, probably as a result of partial in vivo differentiation, and degenerative cells increased after 2 to 3 weeks of continuous in vivo As 2 O 3 treatment when leukemic promyelocytes decreased. In conclusion, combination of induction of apoptosis and partial differention could be the main cellular mechanisms of As 2 O 3 in the treatment of APL, and PML-RARα could play an important role in determining the specific effects of As 2 O 3 on APL cells.