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Oncotarget. 2016 Apr 12;7(15):20788-800. doi: 10.18632/oncotarget.7878.

Radiation therapy generates platelet-activating factor agonists.

Author information

1
Department of Pharmacology and Toxicology, Boonshoft School of Medicine at Wright State University, Dayton, OH, USA.
2
Department of Pharmacology, University of Colorado Health Sciences Center, Aurora, CO, USA.
3
Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA.
4
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
5
Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.
6
Department of Biostatistics, Wright State University, Dayton, OH, USA.
7
The Dayton V.A. Medical Center, Dayton, OH, USA.

Abstract

Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens.

KEYWORDS:

antioxidants; cyclooxygenase type 2 enzyme; oxidized glycerophosphocholines; platelet-activating factor; radiation therapy

PMID:
26959112
PMCID:
PMC4991492
DOI:
10.18632/oncotarget.7878
[Indexed for MEDLINE]
Free PMC Article

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