Oxaloacetate as a Holy Grail Adjunctive Treatment in Gliomas: A Revisit to Metabolic Pathway.

Abstract

India experiences a significant amount of morbidity and mortality due to gliomas particularly glioblastoma multiforme (GBM), which ranks among the worst cancers. Oxaloacetate (OAA) is a human keto acid that is central to cellular metabolism; it has been recognized by the US FDA for use in GBM patients, triggering a review to revisit the cellular mechanism of its therapeutic action.Various cellular and molecular studies have proposed that instead of fueling the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), gliomas prefer to use glycolysis (the Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis. A study found that oxaloacetate (OAA) inhibits human lactate dehydrogenase A (LDHA) in cancer cells, reversing the Warburg effect. Studies revealed that OAA supplementation reduced Warburg glycolysis, improved neuronal cell bioenergetics, and triggered brain mitochondrial biogenesis, thereby enhancing the efficacy of standard treatment. Similarly, OAA has been found in preclinical investigations to be able to decrease tumor development and survival rates by blocking the conversion of glutamine to alpha-ketoglutarate (alpha-KG) in the TCA cycle and lowering nicotinamide adenine dinucleotide phosphate (NADPH) levels. OAAis a safe adjuvant that has the potential to be an effective therapy in gliomas when combined with temozolomide (TMZ) chemotherapy and routine surgery.