Selenium supplementation protects cancer cells from the oxidative stress and cytotoxicity induced by the combination of ascorbate and menadione sodium bisulfite

The combination of ascorbate (vitamin C) and menadione sodium bisulfite (MSB, vitamin K3), here called VC/VK3 (also named Apatone®, or M/A), has shown selective cytotoxicity in cancer cells and is under clinical investigation as a cancer therapy. However, the mechanisms of VC/VK3-induced cell death are not fully understood. In this in vitro study using human glioblastoma and non-transformed glial cell lines, we found that VC/VK3 caused higher toxicity in cancer cells in an H₂O₂- and iron-dependent manner, suggesting that ferroptosis may play a role in the cell death process. Furthermore, selenium supplementation significantly protected cancer cells from VC/VK3 treatment concomitantly with enhanced expression levels and enzymatic activity of antioxidant selenoproteins, including thioredoxin reductases (TXNRDs) and glutathione reductases (GPXs). We also found that VC/VK3 competes for electrons with thioredoxin (TXN), impairing peroxiredoxin 1 (PRDX1) in cells. Finally, chemically inhibiting TXNRDs or the glutathione-dependent antioxidant systems exaggerated the toxicity of VC/VK3. Overall, this study elucidated parts of the cell death mechanisms of VC/VK3 and identified combination strategies to overcome selenium-mediated resistance, advancing the translational potential of this prooxidant treatment.