Radiation-Induced Lipid Peroxidation Triggers Ferroptosis and Synergizes with Ferroptosis Inducers

Abstract

Although radiation is widely used to treat cancers, resistance mechanisms often develop and involve activation of DNA repair and inhibition of apoptosis. Therefore, chemicals that exploit alternative cell death pathways to selectively sensitize cancer cells to radiation are valuable. We report here that ferroptosis, a form of non-apoptotic cell death driven by lipid peroxidation, is partly responsible for radiation-induced cancer cell death. Moreover, small molecules activating ferroptosis synergize with radiation to induce cell death in several cancer types by enhancing lipid peroxidation, but do not increase DNA damage or apoptosis activation. Ferroptosis inducers synergized with cytoplasmic irradiation, but not nuclear irradiation. Finally, administration of ferroptosis inducers enhanced the anti-tumor effect of radiation in a murine xenograft model, and in human patient-derived models of lung adenocarcinoma and glioma. These results suggest that ferroptosis inducers may be effective radiosensitizers that can expand the efficacy and range of indications for radiation therapy.