Abstract

Introduction. Ferroptosis, an iron-dependent lethal peroxidation of phospholipids, is a form of nonapoptotic cell death identified as a type of death that could be activated in certain types of cancer. On the other hand, a popular hypothesis suggests that mega doses of reduced form of vitamin C, ascorbic acid (AA), can act as an anti-cancer pro-drug. However, several cell types are resistant to mega doses of AA, such as glioblastoma. Strikingly, treatment with the oxidized form of vitamin C, dehydroascorbic acid (DHA), induces cell death by consumption of GSH, ROS and lipid ROS in certain types of cell. To date, it is unknown how to sensitize cells resistant to ferroptosis to this type of death. Here, we show that glioblastoma cell treated with Erastin-DHA are sensitized to death by ferroptosis. Materials and methods. Human glioblastoma Cell (U87) and normal primary rat astrocytes were treated with Erastin, RSL-3, overload of iron, glutamate and cotreated with oxidized form of vitamin C, DHA. Ferrostatin and -mercaptoethanol, was used as an inhibitor of ferroptosis. Additionally, we evaluate the participation of autophagy in the sensitization to the ferroptosis by DHA. Cell death was monitored by the incorporation of Sitox green with real-time live-cell microscopy using an IncuCyte S3 system. Total (CellRox), mitochondrial ROS (mitosox) and lipid ROS were determined by FACS. Using superresolution microscopy and mitotracker, we analyzed mitochondrial fragmentation. Results. We found that human glioblastoma cells are resistant to the conventional ferroptosis induction therapies. Interestingly, specifically co-treatment DHA-Erastin sensitizes glioblastomas to ferroptosis. While in primary astrocytes, treatment with DHA inhibits Erastin-induced ferroptosis. Discussion. This data suggests that the administration of DHA-Erastin would be specific for kill tumor cells. Acknowledgements. Fondecyt 1181243; CMA BIO BIO, PIA-CONICYT, ECM-12.