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

Although radiation is widely used to treat cancers, resistance mechanisms often develop and involve activation of DNA repair and inhibition of apoptosis. Therefore, compounds that sensitize cancer cells to radiation via alternative cell death pathways are valuable. We report here that ferroptosis, a...

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Bibliographic Details
Published in:ACS chemical biology 2020-02, Vol.15 (2), p.469-484
Main Authors: Ye, Ling F, Chaudhary, Kunal R, Zandkarimi, Fereshteh, Harken, Andrew D, Kinslow, Connor J, Upadhyayula, Pavan S, Dovas, Athanassios, Higgins, Dominique M, Tan, Hui, Zhang, Yan, Buonanno, Manuela, Wang, Tony J. C, Hei, Tom K, Bruce, Jeffrey N, Canoll, Peter D, Cheng, Simon K, Stockwell, Brent R
Format: Article
Language:English
Subjects:
Amino Acid Transport System y+ - metabolism
Animals
Antineoplastic Agents - therapeutic use
Carbolines - therapeutic use
Cell Line, Tumor
Ferroptosis - drug effects
Gamma Rays
Humans
Imidazoles - therapeutic use
Ketones - therapeutic use
Lipid Peroxidation - drug effects
Lipid Peroxidation - radiation effects
Mice, Nude
Neoplasms - drug therapy
Neoplasms - radiotherapy
Piperazines - therapeutic use
Radiation-Sensitizing Agents - therapeutic use
Sorafenib - therapeutic use
Xenograft Model Antitumor Assays
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Summary:Although radiation is widely used to treat cancers, resistance mechanisms often develop and involve activation of DNA repair and inhibition of apoptosis. Therefore, compounds that sensitize cancer cells to radiation via alternative cell death pathways are valuable. We report here that ferroptosis, a form of nonapoptotic cell death driven by lipid peroxidation, is partly responsible for radiation-induced cancer cell death. Moreover, we found that small molecules activating ferroptosis through system xc – inhibition or GPX4 inhibition synergize with radiation to induce ferroptosis in several cancer types by enhancing cytoplasmic lipid peroxidation but not increasing DNA damage or caspase activation. Ferroptosis inducers synergized with cytoplasmic irradiation, but not nuclear irradiation. Finally, administration of ferroptosis inducers enhanced the antitumor 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.
ISSN:1554-8929
1554-8937
DOI:10.1021/acschembio.9b00939