Radiation therapy generates platelet-activating factor agonists

// Ravi P. Sahu 1 , Kathleen A. Harrison 2 , Jonathan Weyerbacher 3 , Robert C. Murphy 2 , Raymond L. Konger 4 , Joy Elizabeth Garrett 5 , Helen Jan Chin-Sinex 5 , Michael Edward Johnston II 3 , Joseph R. Dynlacht 5 , Marc Mendonca 5 , Kevin McMullen 5 , Gengxin Li 6 , Dan F. Spandau 3 , Jeffrey B. Travers 1, 3, 7 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 Correspondence to: Ravi P. Sahu, e-mail: ravi.sahu@wright.edu Keywords: radiation therapy, oxidized glycerophosphocholines, platelet-activating factor, cyclooxygenase type 2 enzyme, antioxidants Received: November 30, 2015     Accepted: February 06, 2016     Published: March 03, 2016 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.