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.
Highlights
Radiotherapy (RT) is an important modality in the management of many types of cancer [1]
Similar to our published findings examining platelet-activating factor (PAF)-R biochemical activity generated in human epithelial tumor cells or human skin in response to ultraviolet B (UVB) [15, 17, 26], preincubation of melanoma cells with antioxidants vitamin C or N-acetylcysteine (NAC) blocked ionizing radiation (IR)-generated platelet-activating factor-receptor (PAF-R) agonistic activity (Figure 2)
The present studies demonstrate that IR-generated PAF-R agonistic activity is diminished by antioxidants, but structural characterization of this activity reveals oxidized GPC (ox-GPC) known to be produced nonenzymatically
Summary
Radiotherapy (RT) is an important modality in the management of many types of cancer [1]. Several groups, including ours, have demonstrated suppression of host immunity in the presence of various pro-oxidative stressors through a mechanism involving the lipid mediator Platelet-activating Factor (1-alkyl-2-acetyl-glycerophosphocholine; PAF) [4,5,6,7,8]. Prooxidative stressors including aromatic hydrocarbons found in jet fuel, chemotherapeutic agents, cigarette smoke, and ultraviolet B (UVB) radiation generate ROS that can act directly on glycerophosphocholines (GPC) to produce oxidized GPC (ox-GPC) which are potent PAF-receptor (PAF-R) agonists [9,10,11,12,13,14]. Like native PAF, these Ox-GPCs are metabolically unstable and their half-lives in tissue/blood are measured in minutes [20,21]
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