Diphenyl Diselenide and Temozolomide: Downregulation of Inflammatory, Redox, and Tumor-Associated Pathways in Glioblastoma.

UNLABELLED: Glioblastoma (GBM) is the most common and lethal primary brain tumor, originating from glial cells and classified as grade IV by the World Health Organization (WHO). Standard treatment includes resection, radiotherapy, and the use of temozolomide (TMZ), a DNA-alkylating agent; however, therapeutic success is limited due to tumor heterogeneity and resistance mechanisms. Selenium (Se) is an essential element involved in selenoprotein formation, with reported anti-inflammatory, antioxidant, and antitumor activities. Among organoselenium compounds (OrganoSe), Diphenyl Diselenide (DPDS) has demonstrated antitumor, antioxidant, and anti-inflammatory properties, but its effects in human GBM are underexplored. Here, we investigated, for the first time, the antitumor capacity of DPDS, both alone and in combination with TMZ, in U87-MG cells. We evaluated cell viability, density, migration, biochemical and molecular pathways, including oxidative stress, inflammation, apoptosis, hypoxia response, epigenetic regulation, cell cycle, DNA damage response, and epithelial–mesenchymal transition (EMT). DPDS (20 µM) in combination with TMZ (100 µM) reduced cell viability and density. Co-exposure decreased cellular migration and oxidative stress markers (ROS production, SOD, and CAT activities). Gene expression analysis revealed downregulation of genes related to redox defense and inflammatory signaling, such as NRF2, KEAP1, GPX1, GPX4, TRXR1, SELENOS, SELENOK, SELENOI, NFKB1, IL6, IL-1B, TNFα, PTGS2, BAX, BAD, BCL-2, HIF1A, HDAC4, NEK1, NEK2, and SNAIL1. The results indicate that DPDS, particularly in combination with TMZ, attenuated pro-inflammatory and antioxidant profiles and interfered with pathways critical for GBM survival.

GRAPHICAL ABSTRACT: [Image: see text]