N-acetylcysteine dual and antagonistic effect on cadmium cytotoxicity in human leukemia cells

[Display omitted] •ROS played a marginal role in Cd2+ mediated cell death in human leukemia cells.•NAC formed stable complexes [Cd(NAC)2] with Cd2+ at physiological pH.•Complete complexation of Cd2+was the main mechanism that prevented Cd2+ cytotoxicity.•Unexpectedly, partial Cd2+complexation by NAC dramatically enhanced its cytotoxicity. Although cadmium (Cd2+) is unable to form reactive oxygen species (ROS) directly, many of its adverse effects are connected to increased ROS generation resulting in cell death. In support of this supposition, a large number of studies have shown protective effects of antioxidants such as N-acetylcysteine (NAC) against cadmium induced cytotoxicity. Here, we describe the cytotoxic effects of Cd2+ on human leukemia U937 and K562 cells that were not mediated by oxidative stress. Surprisingly, we observed that addition of low concentrations of NAC can drastically potentiate cadmium cytotoxicity solely via ROS production. However, all adverse effects of the metal were prevented by NAC at high concentrations. Detailed analysis indicated that the protective effect of NAC was mediated by its ability to form stable complex with cadmium [Cd(NAC)2]. In conclusion, NAC exhibits dual and antagonistic effects on Cd2+ cytotoxicity in human leukemia cells.