Radiation-Induced Lipid Peroxidation Triggers Ferroptosis and Synergizes with Ferroptosis Inducers
Number of pages: 62Posted: 07 Nov 2019
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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. 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 a human patient-derived model of lung adenocarcinoma. These results suggest that ferroptosis inducers may be effective radiosensitizers that can expand the efficacy and range of indications for radiation therapy.
Ye, Ling F. and Chaudhary, Kunal R. and Zandkarimi, Fereshteh and Harken, Andrew D. and Kinslow, Connor J. and Upadhyayula, Pavan S. and Dovas, Athanassios and Higgins, Dominique M. and Tan, Hui and Zhang, Yan and Buonanno, Manuela and Wang, Tony J. C. and Hei, Tom K. and Bruce, Jeffrey N. and Canoll, Peter and Cheng, Simon K. and Stockwell, Brent R., Radiation-Induced Lipid Peroxidation Triggers Ferroptosis and Synergizes with Ferroptosis Inducers (October 23, 2019). Available at SSRN: https://ssrn.com/abstract=3474050 or http://dx.doi.org/10.2139/ssrn.3474050
This version of the paper has not been formally peer reviewed.
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