Tetraarsenictetrasulfide and Arsenic Trioxide Exert Synergistic Effects on Induction of Apoptosis and Differentiation in Acute Promyelocytic Leukemia Cells

Since arsenic trioxide (As(3+)) has been successfully used in the treatment of acute promyelocytic leukemia (APL), its adverse effects on patients have been problematic and required a solution. Considering the good therapeutic potency and low toxicity of tetraarsenictetrasulfide (As(4)S(4)) in the treatment of APL, we investigated the effects of combining As(4)S(4) and As(3+) on the apoptosis and differentiation of NB4 and primary APL cells. As(4)S(4), acting similarly to As(3+), arrested the G(1)/S transition, induced the accumulation of cellular reactive oxygen species, and promoted apoptosis. Additionally, low concentrations of As(4)S(4) (0.1–0.4 μM) induced differentiation of NB4 and primary APL cells. Compared with the As(4)S(4)- or As(3+)-treated groups, the combination of As(4)S(4) and As(3+) obviously promoted apoptosis and differentiation of NB4 and primary APL cells. Mechanistic studies suggested that As(4)S(4) acted synergistically with As(3+) to down-regulate Bcl-2 and nuclear factor-κB expression, up-regulate Bax and p53 expression, and induce activation of caspase-12 and caspase-3. Moreover, the combination of low concentrations of As(4)S(4) and As(3+) enhanced degradation of the promyelocytic leukemia-retinoic acid receptor α oncoprotein. In summary, As(4)S(4) and As(3+) synergistically induce the apoptosis and differentiation of NB4 and primary APL cells.