Role of Selenium-Dependent Glutathione Peroxidases (Seleno-GPxs) in Radio-Modulation: Lessons for Radiation Oncology

Factors modulating cellular radiosensitivity can be of huge relevance considering the growing use of ionizing radiation in therapy and diagnosis. Since reactive oxygen species (ROS) primarily contribute to radiation-induced toxicity, antioxidant enzymes involved in ROS detoxification are expected to be influencing cellular radiosensitivity. Among antioxidant enzymes, glutathione peroxidase (GPx) plays an important role in detoxifying hydroperoxides including lipid hydroperoxides. As lipid hydroperoxides are known for propagating radiation injury, understating the influence of the alteration in expression/activity level of GPx on cellular radiosensitivity has received a lot of attention among researchers. Of the eight isozymes of GPx, at least four, including GPx1, GPx2, GPx3, and GPx4 in mammals, contain selenocysteine (Sec) in their active site. The biosynthesis of Sec and its subsequent incorporation into seleno-GPxs are regulated by the bioavailable selenium pool (hydrogen selenide). The present review article focuses on summarizing the physiological role of seleno-GPxs and their synthetic mimics (mainly organoselenium compounds) in the radiation response of preclinical model systems. Briefly, GPx intervention studies through genetic manipulation or selenium supplementation or synthetic mimic have conveyed contradictory viewpoints, with some reports showing a positive role of seleno-GPxs in offering radioresistance, while others reject such claims. Moreover, the recent evidences suggest that the isozymes of seleno-GPx may contribute differently to tissue-specific radioresistance. All these inconsistent findings are reflective of the need for further investigation in this evolving field.