In this study, we investigated the role of reactive oxygen species (ROS) in Fas-induced cell death in human astrocytoma cells. Fas activation increased intracellular ROS levels in a NADPH oxidase- and caspase-dependent manner. ROS inhibitors such as N-acetyl cysteine (NAC) and caffeic acid phenethyl ester (CAPE) dramatically sensitized astocytoma cells to Fas-induced loss of mitochondrial transmembrane potential and subsequent cell death, which were abrogated by pretreatment with z-VAD-fmk, a broad-spectrum caspase inhibitor. These results collectively indicate that NAC and CAPE sensitize astrocytoma cells to Fas-induced apoptosis in a redox-dependent manner, suggesting a potential use in the treatment of malignant brain tumors. (C) 2007 Elsevier Ireland Ltd. All rights reserved.