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Commentary Open Access
Volume 6 | Issue 1 | DOI: https://doi.org/10.33696/Neurol.6.104

Is MGMT Gene Silencing an Opportunity for Enhanced Metformin Action in Glioblastoma cells?

  • 1Faculty of Medicine and Health Sciences, McGill University, 3605 Rue de la Montagne, Montreal, H3G 2M1, Canada
  • 2Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, 3801 Rue University, Montreal, H3A 2B4, Canada
+ Affiliations - Affiliations

Corresponding Author

Roberto Jose Diaz, roberto.diaz@mcgill.ca

Received Date: October 21, 2024

Accepted Date: November 25, 2024

Abstract

Isocitrate dehydrogenase 1 (IDH1)-wild type glioblastoma (GBM) constitutes about 12-15% of primary central nervous system tumors. The 5-year survival remains dismal at less than 5% due to the limited options available in the management of GBM patients. Metformin (N, N-dimethyl biguanide), a medication used primarily in the management of patients with type 2 diabetes mellitus, showed anti-proliferative actions in the management of various tumor cells, including GBM. The temozolomide (TMZ)-based genotoxic management of GBM patients elicits DNA damage response (DDR) pathways that limit the efficacy of TMZ and induce resistance. Tumors with a methylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter status may be more dependent on DDR pathways due to the reduced DNA repair capability. Metformin can reinforce an integrative approach in GBM management in conjunction with TMZ by inhibiting several key DDR pathways of metabolism and growth. In addition to inhibition of the mitochondrial complex I, uncoupling glycolysis from oxidative phosphorylation, metformin AMP-activated Protein Kinase (AMPK)-mediated inhibition of Akt signaling can manipulate multiple key metabolic cellular processes. Our commentary proposes that metformin may exert an asymmetrical effect, preferentially inhibiting GBM cells with MGMT promoter methylation, by exploiting differences in metabolism that extend to glycolysis, oxidative phosphorylation, lipolysis, sphingolipid metabolism, and amino acid transport and sensing. We also highlight an emerging role for metformin in epigenetic modification through regulation of homocysteine metabolism and 2-Hydroxyglutarate bioavailability. In this commentary, expanding on our recent study showing that metformin treatment is associated with improved survival in GBM patients with a methylated MGMT promoter, we explore how the targets of metformin in GBM may differ depending on the MGMT methylation status. Our commentary invites a better examination of the action of metformin in GBM and highlights its therapeutic potential in conjunction with the molecular signature of GBM. 

Keywords

Glioblastoma, Metformin, MGMT, AMPK, Molecular determinants

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