Tetraarsenictetrasulfide and arsenic trioxide exert synergistic effects on induction of apoptosis and differentiation in acute promyelocytic leukemia cells

Abstract

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.