Vitamin C enhanced erastin-induced ferroptosis in drug-resistant colorectal cancer cells and in CAM-derived xenografts

Recent studies indicated that the induction of ferroptosis, a type of non-apoptotic and iron-dependent form of cell death, could be a promising therapeutic approach for eradicating drug-resistant colorectal cancer (CRC) cells. Based on our previous findings indicating that the downregulation of human ribosomal protein L3 (uL3) positively correlates with chemoresistance in CRC cells lacking active p53 (REF), we investigated the susceptibility of this cell line to erastin, as a ferroptosis inducer, in combination with vitamin C. In this study, we revealed that the low expression state of uL3 renders p53-delete CRC cells more vulnerable to ferroptosis, and the combined treatment of erastin and vitamin C acts synergistically to induce ferroptotic cell death. Specifically, we evaluated intracellular iron, glutathione, reactive oxygen species levels along with the analysis of ferroptosis-related markers. In vivo experiments showed that erastin and vitamin C can significantly reduce tumor growth in xenografts derived from uL3-silenced CRC cells in the Chorioallantoic Membrane (CAM) model. In summary, the combination of erastin and vitamin C exerts a synergistic effect to induce ferroptosis in CRC cells that have low amounts of uL3 and lacking functional p53, thus providing a novel therapeutic strategy for CRC treatment.