Dimethyl fumarate combined with cisplatin at subcytotoxic doses sensitizes cervical cancer toward ferroptosis and apoptosis through GSH restriction and p53 (re)activation

: Cervical cancer is one of the leading causes of tumor-related deaths among women. Chemotherapy in cervical cancer is mainly based on cisplatin, but this drug has limited efficacy; therefore, alternative treatment options are needed. Ferroptosis represents a novel form of cell death. In cervical epithelium, ferroptosis occurs in the early neoplastic stages of papillomavirus infection but shifts to evasion in carcinoma. Combination therapy has the potential to enhance cancer cell death and overcome resistance development. Herein we demonstrate that dimethyl fumarate (DMF), a Food and Drug Administration (FDA)-approved anti-inflammatory drug, induces ferroptosis in cervical cancer cells in a dose-dependent manner and inhibits growth in spheroid models. Cotreatment with DMF and cisplatin significantly decreases cell viability compared to either drug alone. Under DMF/cisplatin combination, cervical cancer cells underwent to glutathione depletion and p53 (re)activation, leading to cell death by both ferroptosis and apoptosis. We found a p53-mediated downregulation of the Solute Carrier Family 7 Member 11 (SLC7A11)/Cystine/Glutamate Transporter (xCT) expression and glutathione levels. Our results suggest that combined administration of DMF and cisplatin, by targeting the dependency of cervical cancer cells on glutathione and (re)activating p53, represents a promising anticancer therapeutic strategy.