Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment

Cristina Banella, Gianfranco Catalano, Serena Travaglini, Elvira Pelosi, Tiziana Ottone, Alessandra Zaza, Gisella Guerrera, Daniela Fabiana Angelini, Pasquale Niscola, Mariadomenica Divona, Luca Battistini, Maria Screnci, Emanuele Ammatuna, Ugo Testa, Clara Nervi, Maria Teresa Voso, Nelida Ines Noguera

Research output: Contribution to journalArticlepeer-review

Abstract

In the present study, we characterized the metabolic background of different Acute Myeloid Leukemias’ (AMLs) cells and described a heterogeneous and highly flexible energetic metabolism. Using the Seahorse XF Agilent, we compared the metabolism of normal hematopoietic progenitors with that of primary AML blasts and five different AML cell lines. We assessed the efficacy and mechanism of action of the association of high doses of ascorbate, a powerful oxidant, with the metabolic inhibitor buformin, which inhibits mitochondrial complex I and completely shuts down mitochondrial contributions in ATP production. Primary blasts from seventeen AML patients, assayed for annexin V and live/dead exclusion by flow cytometry, showed an increase in the apoptotic effect using the drug combination, as compared with ascorbate alone. We show that ascorbate inhibits glycolysis through interfering with HK1/2 and GLUT1 functions in hematopoietic cells. Ascorbate combined with buformin decreases mitochondrial respiration and ATP production and downregulates glycolysis, enhancing the apoptotic effect of ascorbate in primary blasts from AMLs and sparing normal CD34+ bone marrow progenitors. In conclusion, our data have therapeutic implications especially in fragile patients since both agents have an excellent safety profile, and the data also support the clinical evaluation of ascorbate–buformin in association with different mechanism drugs for the treatment of refractory/relapsing AML patients with no other therapeutic options.

Original languageEnglish
Article number2565
JournalCancers
Volume14
Issue number10
DOIs
Publication statusPublished - May 1 2022

Keywords

  • Acute Myeloid Leukemia
  • ascorbate
  • buformin
  • GLUT1
  • glycolysis
  • hexokinase 1/2
  • metabolism
  • OXPHOS
  • pharmacologic activity
  • Seahorse XF

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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