Abstract

The anti-cancer potential of disulfiram derivatives is increasingly recognized, yet the precise mechanisms by which they induce programmed cell death remain under investigation. This study explores the cellular and molecular events underlying the initiation of paraptosis-like death in HEp-2 tumor cells following treatment with novel oxidized disulfiram derivatives. Our primary objective was to determine if the cytotoxic effects are mediated through alterations in the epigenetic landscape, specifically focusing on the regulation of the histone code. Using a combination of cell viability assays, morphological analysis, and molecular techniques, we confirmed that the oxidized derivatives effectively trigger a non-apoptotic, paraptosis-like cell death characterized by extensive vacuolization and mitochondrial swelling. Crucially, we identified early and significant changes in the global and localized patterns of histone modifications, including acetylation and methylation marks, preceding the full manifestation of cell death. These findings suggest that the oxidized disulfiram derivatives act as potent epigenetic modulators, disrupting the delicate balance of the histone code to initiate the paraptotic cascade. This mechanism highlights a novel therapeutic vulnerability in HEp-2 cells and provides a foundation for developing next-generation, epigenetically-targeted anti-cancer agents.