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Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs.

Abstract
Metabolomic fingerprint of breast cancer cells treated with the antidiabetic drug metformin revealed a significant accumulation of 5-formimino-tetrahydrofolate, one of the tetrahydrofolate forms carrying activated one-carbon units that are essential for the de novo synthesis of purines and pyrimidines. De novo synthesis of glutathione, a folate-dependent pathway interconnected with one-carbon metabolism was concomitantly depleted in response to metformin. End-product reversal studies demonstrated that thymidine alone leads to a significant but incomplete protection from metformin's cytostatic effects. The addition of the substrate hypoxanthine for the purine salvage pathway produces major rightward shifts in metformin's growth inhibition curves. Metformin treatment failed to activate the DNA repair protein ATM kinase and the metabolic tumor suppressor AMPK when thymidine and hypoxanthine were present in the extracellular milieu. Our current findings suggest for the first time that metformin can function as an antifolate chemotherapeutic agent that induces the ATM/AMPK tumor suppressor axis secondarily following the alteration of the carbon flow through the folate-related one-carbon metabolic pathways.
AuthorsBruna Corominas-Faja, Rosa Quirantes-Piné, Cristina Oliveras-Ferraros, Alejandro Vazquez-Martin, Sílvia Cufí, Begoña Martin-Castillo, Vicente Micol, Jorge Joven, Antonio Segura-Carretero, Javier A Menendez
JournalAging (Aging (Albany NY)) Vol. 4 Issue 7 Pg. 480-98 (Jul 2012) ISSN: 1945-4589 [Electronic] United States
PMID22837425 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Folic Acid Antagonists
  • Hypoglycemic Agents
  • Nucleotides
  • Purines
  • Tumor Suppressor Proteins
  • Carbon
  • Metformin
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases
  • Glutathione
  • Thymidine
Topics
  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases (metabolism)
  • Ataxia Telangiectasia Mutated Proteins
  • Breast Neoplasms (drug therapy, metabolism)
  • Carbon (metabolism)
  • Cell Cycle Proteins (metabolism)
  • DNA-Binding Proteins (metabolism)
  • Female
  • Folic Acid Antagonists (pharmacology)
  • Glutathione (metabolism)
  • Humans
  • Hypoglycemic Agents (pharmacology, therapeutic use)
  • MCF-7 Cells
  • Metabolome
  • Metformin (pharmacology, therapeutic use)
  • Nucleotides (metabolism)
  • Protein Serine-Threonine Kinases (metabolism)
  • Purines
  • Thymidine
  • Tumor Suppressor Proteins (metabolism)

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