Concentration-Dependent Metabolic Effects of Metformin in Healthy and Fanconi Anemia Lymphoblast Cells

Silvia Ravera, Vanessa Cossu, Barbara Anna Tappino, Elena Nicchia, Carlo Dufour, Simona Cavani, Andrea Sciutto, Claudia Bolognesi, Marta Columbaro, Paolo Degan, Enrico Cappelli

Research output: Contribution to journalArticle

Abstract

Metformin (MET) is the drug of choice for patients with type 2 diabetes and has been proposed for use in cancer therapy and for treating other metabolic diseases. More than 14,000 studies have been published addressing the cellular mechanisms affected by MET. However, several in vitro studies have used concentrations of the drug 10-100-fold higher than the plasmatic concentration measured in patients. Here we evaluated the biochemical, metabolic and morphologic effects of various concentrations of MET. Moreover, we tested the effect of MET on Fanconi Anemia (FA) cells, a DNA repair genetic disease with defects in energetic and glucose metabolism, as well as on human promyelocytic leukemia (HL60) cell lines. We found that the response of wild-type cells to MET is concentration dependent. Low concentrations (15 and 150 µM) increase both oxidative phosphorylation and the oxidative stress response, acting on the AMPK/Sirt1 pathway, while the high concentration (1.5 mM) inhibits the respiratory chain, alters cell morphology, becoming toxic to the cells. In FA cells, MET was unable to correct the energetic/respiratory defect and did not improve the response to oxidative stress and DNA damage. By contrast, HL60 cells appear sensitive also at 150 µM. Our findings underline the importance of the MET concentration in evaluating the effect of this drug on cell metabolism and demonstrate that data obtained from in vitro experiments, that have used high concentrations of MET, cannot be readily translated into improving our understanding of the cellular effects of metformin when used in the clinical setting. This article is protected by copyright. All rights reserved.
Original languageEnglish
Pages (from-to)1736-1751
Number of pages16
JournalJournal of Cellular Physiology
Volume233
Issue number2
DOIs
Publication statusPublished - Jul 6 2017

Fingerprint

Fanconi Anemia
Metformin
HL-60 Cells
Oxidative Stress
Inborn Genetic Diseases
AMP-Activated Protein Kinases
Poisons
Oxidative Phosphorylation
Metabolic Diseases
Electron Transport
DNA Repair
Pharmaceutical Preparations
Type 2 Diabetes Mellitus
DNA Damage
Leukemia
Glucose
Cell Line

Keywords

  • Cancerogenesis
  • Fanconi anemia
  • energetic metabolism
  • metformin
  • oxidative stress

Cite this

Concentration-Dependent Metabolic Effects of Metformin in Healthy and Fanconi Anemia Lymphoblast Cells. / Ravera, Silvia; Cossu, Vanessa; Tappino, Barbara Anna; Nicchia, Elena; Dufour, Carlo; Cavani, Simona; Sciutto, Andrea; Bolognesi, Claudia; Columbaro, Marta; Degan, Paolo; Cappelli, Enrico.

In: Journal of Cellular Physiology, Vol. 233, No. 2, 06.07.2017, p. 1736-1751.

Research output: Contribution to journalArticle

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