Involvement of oxidative stress associated with glutathione depletion and p38 mitogen-activated protein kinase activation in arsenic disulfide-induced differentiation in HL-60 cells.

Arsenic disulfide (As₂S₂) has been traditionally used to treat certain types of leukemia. However, a detailed mechanism of action of As₂S₂ is not sufficiently documented. The effects of As₂S₂ on HL-60 cells were therefore investigated by focusing on proliferation, differentiation, generation of reactive oxygen species (ROS), intracellular glutathione (GSH) depletion and activation of p38 mitogen-activated protein kinase (MAPK). As₂S₂ at 0.5-8 μM induced cell differentiation based on an increment in CD11b expression, nitroblue tetrazolium (NBT)-positive cells and cell size change. A transient increase in ROS level along with intracellular GSH level was also observed. p38 MAPK activation gradually increased after ROS generation and was sustained during cell differentiation. Decreased CD11b expression was accompanied by p38 MAPK activation, and a p38 MAPK inhibitor restored CD11b expression. The results suggest that moderate levels of oxidative stress induced by As₂S₂ correlate with HL-60 cell differentiation. Suppression of p38 MAPK can augment the efficacy of As₂S₂ to induce HL-60 cell differentiation.