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

62 Pages Posted: 7 Nov 2019 Sneak Peek Status: Under Review

See all articles by Ling F. Ye

Ling F. Ye

Columbia University - Department of Biological Sciences

Kunal R. Chaudhary

Columbia University - Department of Radiation Oncology

Fereshteh Zandkarimi

Columbia University - Department of Biological Sciences

Andrew D. Harken

Columbia University - Radiological Research Accelerator Facility

Connor J. Kinslow

Columbia University - Department of Radiation Oncology

Pavan S. Upadhyayula

Columbia University - Department of Neurological Surgery

Athanassios Dovas

Columbia University - Departments of Pathology and Cell Biology

Dominique M. Higgins

Columbia University - Department of Neurological Surgery

Hui Tan

Columbia University - Department of Biological Sciences

Yan Zhang

Columbia University - Department of Biological Sciences

Manuela Buonanno

Columbia University - Radiological Research Accelerator Facility

Tony J. C. Wang

Columbia University - Department of Radiation Oncology

Tom K. Hei

Columbia University - Department of Radiation Oncology

Jeffrey N. Bruce

Columbia University - Department of Neurological Surgery

Peter Canoll

Columbia University - Department of Pathology and Cell Biology

Simon K. Cheng

Columbia University - Department of Radiation Oncology

Brent R. Stockwell

Columbia University - Department of Biological Sciences

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Multiple version iconThere are 2 versions of this paper

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.

Keywords: Ferroptosis, radiation, cancer, lipid peroxidation, ROS, glutathione, cell death, microbeam

Suggested Citation

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). CELL-CHEMICAL-BIOLOGY-D-19-00412. Available at SSRN: https://ssrn.com/abstract=3474050 or http://dx.doi.org/10.2139/ssrn.3474050
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Ling F. Ye

Columbia University - Department of Biological Sciences

New York, NY 10027
United States

Kunal R. Chaudhary

Columbia University - Department of Radiation Oncology

New York, NY 10032
United States

Fereshteh Zandkarimi

Columbia University - Department of Biological Sciences ( email )

New York, NY 10027
United States

Andrew D. Harken

Columbia University - Radiological Research Accelerator Facility ( email )

Irvington, NY 10533
United States

Connor J. Kinslow

Columbia University - Department of Radiation Oncology ( email )

New York, NY 10032
United States

Pavan S. Upadhyayula

Columbia University - Department of Neurological Surgery

United States

Athanassios Dovas

Columbia University - Departments of Pathology and Cell Biology

1130 St. Nicholas Ave Rm.1001
New York, NY 10032
United States

Dominique M. Higgins

Columbia University - Department of Neurological Surgery

United States

Hui Tan

Columbia University - Department of Biological Sciences

New York, NY 10027
United States

Yan Zhang

Columbia University - Department of Biological Sciences

New York, NY 10027
United States

Manuela Buonanno

Columbia University - Radiological Research Accelerator Facility ( email )

Irvington, NY 10533
United States

Tony J. C. Wang

Columbia University - Department of Radiation Oncology

New York, NY 10032
United States

Tom K. Hei

Columbia University - Department of Radiation Oncology ( email )

New York, NY 10032
United States

Jeffrey N. Bruce

Columbia University - Department of Neurological Surgery

United States

Peter Canoll

Columbia University - Department of Pathology and Cell Biology

New York, NY 10032
United States

Simon K. Cheng

Columbia University - Department of Radiation Oncology ( email )

New York, NY 10032
United States

Brent R. Stockwell (Contact Author)

Columbia University - Department of Biological Sciences ( email )

New York, NY 10027
United States

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