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Tiron and N-acetyl-L-cysteine (NAC) have been recognized as potential antioxidants capable of inhibiting apoptosis induced by reactive oxygen species (ROS). Although the ROS-scavenging function of tiron and NAC is clear, the mechanism for their regulation of apoptosis is still elusive. Here we demonstrate that tiron increases nuclear factor-kappaB (NF-kappaB)/DNA binding and as a result enhances NF-kappaB transcriptional activity. In contrast, NAC inhibits NF-kappaB activation by reducing inhibitor of kappaB kinase (IKK) activity. Moreover, the expression of an NF-kappaB target gene, the chemokine CXCL1, is promoted by tiron and suppressed by NAC. Finally, tiron confers an antiapoptotic function, while NAC imparts a proapoptotic function in melanoma cells. These functions correlate with the alteration of mitochondrial membrane potential but not ROS production or induction of activating protein-1 (AP-1). This study underscores the potential benefits of regulating NF-kappaB activity in melanoma cells as a therapeutic approach.