Tetraarsenic oxide induces apoptosis in U937 leukemic cells through a reactive oxygen species-dependent pathway

In the present study, we investigated the effect of tetraarsenic oxide (As4O6, 2,4,6,8,9,10-Hexaoxa-1,3,5,7-tetraarsatricyclo[3.3.1.13,7]decane) upon induction of apoptosis in arsenic trioxide (diarsenic oxide, As2O3) resistant U937 leukemic cells. As4O6 induced apoptosis in U937 leukemic cells at much lower concentrations than As2O3 via an early increase of cellular reactive oxygen species (ROS), and a decrease in cellular mitochondrial membrane potential, followed by cytochrome c release and caspase-3 activation. As4O6 generated ROS and induced caspase-3 activation more potently than As2O3 in U937 cells. Incubation of the cells with N-acetyl-L-cysteine and catalase resulted in significant suppression of As4O6-induced apoptotic cell death. These results show that the generation of ROS leads to the consequences associated with apoptosis induced by As4O6. In conclusion, As4O6 might be a new arsenic compound which may induce apoptosis in U937 leukemic cells by activating unique apoptotic signaling mediated by ROS more potently than As2O3, and deserves further evaluation.