We investigated the dose-dependent biphasic effects of arsenic disulfide (As2S2) on the differentiation and apoptosis of HL-60 cells. Cellular reactive oxygen species, glutathione, p38 mitogen-activated protein kinase (MAPK), as well as cell differentiation and apoptosis in HL-60 cells were assessed by flow cytometric analysis. The mean percentage of CD11b-positive cells induced by 8 μM As2S2 was more than 3 times higher than that induced by 16 μM As2S2. Eight μM As2S2 did not induce cell apoptosis, while 16 μM As2S2 induced apoptosis and decreased cell viability. Both 8 and 16 μM As2S2 increased cellular reactive oxygen species. Treatment with 16 μM As2S2 decreased the cellular glutathione levels at 1 h and 3 h after the exposure. The mitochondrial membrane potential depletions were observed in both 8 μM As2S2-induced differentiation and 16 μM As2S2-induced apoptosis. p38 MAPK inhibition enhanced As2S2-induced differentiation, but had little influence on As2S2-induced apoptosis. A moderate oxidative stress induced by 8 μM As2S2 can promote As2S2-induced differentiation, whereas more severe oxidative stress caused by glutathione depletion by 16 μM As2S2 reduced mitochondrial membrane potential, resulting in differentiation attenuation and apoptosis enhancement. p38 MAPK activation resulting from oxidative stress seems to be implicated in negative regulation of cell differentiation, rather than apoptosis, in As2S2-treated HL-60 cells.
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