Phenylarsine oxide (PAO) more intensely induces apoptosis in acute promyelocytic leukemia and As2O3-resistant APL cell lines than As2O3 by activating the mitochondrial pathway

We studied the cytotoxic effect of an organic arsenical compound, phenylarsine oxide (PAO) on an acute promyelocytic leukemia (APL) cell line (NB4) and an As₂O₃-resistant NB4 subline (NB4/As). Cell growth was inhibited by 50% (IC₅₀) upon 2-day treatment with As₂O₃ or PAO at 0.54 and 0.06?μM, respectively in NB4 cells (P?=?0.025), and 2.80 and 0.08?μM, respectively in NB4/As (P?=?0.030). 0.1?μM PAO increased the proportion of hypodiploid cells (50.3%) by a greater degree than the same dose of As₂O₃ (3.8%) in NB4 cells. In NB4 cells, 0.1?μM PAO reduced the mitochondrial transmembrane potential (20.5% in a PI^negative-Rhodamine123^low fraction) by a greater degree than 1?μM As₂O₃ (7.1%). Western blotting showed that 0.1?μM PAO downregulated the expression of both Bcl-2 and Bcl-X_L proteins, whereas I μM As₂O₃ downregulated only Bcl-2 expression. These results suggest that the cytotoxic effect of PAO on an APL cell line and As₂O₃-resistant subline is significantly higher than that of As₂O₃. PAO-induced apoptosis seems to be related to the activation of the mitochondrial pathway and downregulation of both Bcl-2 and Bcl-X_L. PAO is a considerable agent for relapsed/refractory APL and for purging APL cells following stem cell transplantation.