P-5 - Screening for novel inhibitors of glutathione peroxidase

Abstract

Cancer cells have higher basal levels of reactive oxygen species (ROS) production, and altered expression of antioxidant enzymes, when compared to normal cells. At high levels, ROS can cause substantial cellular damage, often leading to cell death, and many cancer therapeutics function through targeting these imbalanced redox systems. Glutathione peroxidases (GPx) protect cells from increased levels of ROS and oxidative stress by coupling the reduction of hydrogen and organic peroxides with the oxidization of glutathione (GSH) to glutathione disulfide (GSSG) [1]. Because of the role of glutathione peroxidases in controlling ROS levels, reducing oxidative stress, and regulating cell death pathways, we are interested in identifying inhibitors of GPx1 and GPx4. Moreover, GPx4 has recently been identified as a unique and important regulator of non-apoptotic cell death pathway, ferroptosis [2]. Using a novel method of recombinant GPx expression [3] we are developing an assay amenable to high-throughput screening of small molecules targeting GPx, and will characterize the identified inhibitors as potential chemotherapeutics for treating Glioblastoma Multiforme.