Expression of Antioxidant Defense Genes Determines Synergistic Ferroptosis Induction by the Combination of Erastin and Omega-3 Docosahexaenoic Acid in Prostate Cancer Cells

Ferroptosis is considered a promising strategy for inducing the death of tumor cells. However, the effectiveness of known ferroptosis inducers, such as erastin, is in some cases limited, which stimulates the search for new combined application strategies. In this study, the combined effect of erastin and docosahexaenoic acid (DHA) on prostate cancer cells was examined over time. It was shown that the combination of these agents is more toxic compared to their separate use for all tumor cells considered. At the same time, known ferroptosis inhibitors, ferrostatin-1 and deferoxamine, effectively prevented cell death, indicating the specificity of the mechanism of action. Transcriptomic analysis of cell lines differing in sensitivity to the combination revealed activation of antioxidant systems in more resistant cells (in particular, pronounced expression of the NQO1 and GCLM genes responsible for the reduction of quinones to hydroquinones and the synthesis of glutathione, respectively). The obtained results indicate the high synergistic potential of the erastin-DHA combination for ferroptosis induction and open new possibilities for the development of combined approaches to the therapy of resistant tumors.