N-acetylcysteine Can Induce Massive Oxidative Stress, Resulting in Cell Death with Apoptotic Features in Human Leukemia Cells.

N-acetylcysteine (NAC), often used as an antioxidant-scavenging reactive oxygen species (ROS) in vitro, was recently shown to increase the cytotoxicity of other compounds through ROS-dependent and ROS-independent mechanisms. In this study, NAC itself was found to induce extensive ROS production in human leukemia HL-60 and U937 cells. The cytotoxicity depends on ROS-modulating enzyme expression. In HL-60 cells, NAC activated to produce superoxide (O•). Its subsequent conversion into HO by superoxide dismutase 1 and 3 (, ) and production of ClO from HO by myeloperoxidase () was necessary for cell death induction. While the addition of extracellular potentiated NAC-induced cell death, extracellular catalase () prevented cell death in HL-60 cells. The inhibitor partially reduced the number of dying HL-60 cells. In U937 cells, the weak cytotoxicity of NAC is probably caused by lower expression of , , , and by the absence of MOP expression. However, even here, the addition of extracellular induced cell death in U937 cells, and this effect could be reversed by extracellular . NAC-induced cell death exhibited predominantly apoptotic features in both cell lines. Conclusions: NAC itself can induce extensive production of O• in HL-60 and U937 cell lines. The fate of the cells then depends on the expression of enzymes that control the formation and conversion of ROS: , , and . The mode of cell death in response to NAC treatment bears apoptotic and apoptotic-like features in both cell lines.