The Antioxidant Glycolysis Inhibitor (Citric Acid) Induces a Dose-dependent Caspase-mediated Apoptosis and Necrosis in Glioma Cells

Background: Glioma tumors are still a big challenge being incurable with current chemotherapy and radiotherapy treatments. Surgical treatment of glioma needs adjuvant effective targeting therapy for better glioma cell treatment. Citrate is a well-known antioxidant organic acid abundant in citrus fruits and is an inhibitor of glycolysis through targeting the glycolytic enzyme phosphofructokinase, one of the key enzymes of glycolysis. Citrate is a natural product that is formed inside mitochondria during Krebs cycle to the extent that Krebs cycle is often referred to as citric acid cycle. It was reported that glioma cells are driven by glycolysis where glioma cells upregulates the expression of glycolysis genes and enzymes. Objectives: This aim is to investigate effect of citrate on glioma cells viability, morphology and moge of glioma-induced cell death. Methodology: In this study, citrate-induced glioma cell death was investigated using MTT assay, western blot analysis and flowcytometric evaluation was done to C6 glioma cells. Results: Citrate induced a potent anti-glioma effect by significantly decreasing viability of C6 glioma cells in a dose-dependent manner. Flow cytometric analysis revealed that at 5 mM, citrate induced a caspase-dependent apoptotic glioma cell death. Higher doses of citrate (9 mM) induced necro-apoptotic glioma cell death. Conclusion: citrate may be a promising therapeutic treatment for glioma and glioblastoma. Citrate-rich fruits are strongly recommended as a nutritional treatment for glioma patients.