Metabolic consequences of erastin-induced ferroptosis in human ovarian cancer cells: an untargeted metabolomics study.

Introduction: Ovarian cancer has been difficult to cure due to acquired or intrinsic resistance and therefore, newer or more effective drugs/approaches are needed for a successful treatment in the clinic. Erastin (ER), a ferroptosis inducer, kills tumor cells by generating and accumulating reactive oxygen species (ROS) within the cell, resulting in an iron-dependent oxidative damage-mediated ferroptotic cell death. Methods: We have utilized human ovarian cancer cell lines, OVCAR-8 and its adriamycin-selected, multi-drug resistance protein (MDR1)-expressing NCI/ADR-RES, both equally sensitive to ER, to identify metabolic biomarkers of ferroptosis. Results: Our studies showed that ER treatment rapidly depleted cellular glutathione and cysteine and enhanced formation of ophthalamate (OPH) in both cells. Opthalalmate has been proposed to be a biomarker of oxidative stress in cells. Our study also found significant decreases in cellular taurine, a natural antioxidant in cells. Additionally, we found that ER treatment decreased cellular levels of NAD+/NADP+, carnitines and glutamine/glutamate in both cells, suggesting significant oxidative stress, decrease in energy production, and cellular and mitochondrial disfunctions, leading to cell death. Conclusion: Our studies identified several potential biomarkers of ER-induced ferroptosis including OPH, taurine, NAD+, NADP+ and glutamate in ovarian cancer cells. Identifying specific metabolic biomarkers that are predictive of whether a cancer is susceptible to ferroptosis will help us devise more successful treatment modalities.