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

Abdul Samad1, Rajaram Samant2, K Venkateshwara Rao3

  • 1Department of Medical Affairs, Celagenex Research (India) Private Limited, Thane, IND.

Cureus
|December 18, 2023
PubMed

Insights

Oxaloacetate (OAA) may reverse the Warburg effect in glioblastoma multiforme (GBM) by inhibiting lactate dehydrogenase A. This keto acid shows potential as a safe adjuvant therapy for brain tumors, enhancing standard treatments.

Area of Science:

  • Biochemistry
  • Oncology
  • Neuroscience

Background:

  • Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with significant mortality in India.
  • Cancer cells, including GBM, often rely on glycolysis (Warburg effect) for energy and biosynthesis, rather than oxidative phosphorylation.
  • Oxaloacetate (OAA), a key metabolic keto acid, has FDA recognition for GBM patient use, prompting investigation into its therapeutic mechanisms.

Purpose of the Study:

  • To investigate the cellular mechanisms by which oxaloacetate (OAA) exerts therapeutic effects in glioma, particularly glioblastoma multiforme (GBM).
  • To evaluate OAA's potential to reverse the Warburg effect and improve cellular bioenergetics in brain cancer.
  • To assess OAA's efficacy as an adjuvant therapy when combined with standard GBM treatments.

Main Methods:

  • In vitro studies examining OAA's effect on lactate dehydrogenase A (LDHA) activity in cancer cells.
  • Analysis of cellular metabolism, including glycolysis and tricarboxylic acid (TCA) cycle activity, following OAA supplementation.
  • Preclinical investigations into OAA's impact on tumor development, survival rates, and key metabolic pathways like glutamine conversion and NADPH levels.

Main Results:

  • Oxaloacetate (OAA) was found to inhibit human lactate dehydrogenase A (LDHA), effectively reversing the Warburg effect in cancer cells.
  • OAA supplementation reduced Warburg glycolysis, enhanced neuronal cell bioenergetics, and promoted brain mitochondrial biogenesis.
  • Preclinical studies indicated that OAA decreases tumor growth and survival by inhibiting glutamine to alpha-ketoglutarate (alpha-KG) conversion and lowering NADPH levels.

Conclusions:

  • Oxaloacetate (OAA) demonstrates a potential therapeutic mechanism in gliomas by targeting cancer cell metabolism.
  • OAA acts as a safe adjuvant, capable of enhancing standard GBM treatments like temozolomide (TMZ) chemotherapy and surgery.
  • Further research into OAA could lead to improved therapeutic strategies for glioblastoma multiforme.
Keywords:
adjunctive therapyalter warburg effectglutamate excitotoxicityoxaloacetateglioma

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