Cellular and Molecular Life Sciences

, 64:1290

Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis

  • A. Isakovic
  • L. Harhaji
  • D. Stevanovic
  • Z. Markovic
  • M. Sumarac-Dumanovic
  • V. Starcevic
  • D. Micic
  • V. Trajkovic
Research Article

DOI: 10.1007/s00018-007-7080-4

Cite this article as:
Isakovic, A., Harhaji, L., Stevanovic, D. et al. Cell. Mol. Life Sci. (2007) 64: 1290. doi:10.1007/s00018-007-7080-4

Abstract.

The present study reports for the first time a dual antiglioma effect of the well-known antidiabetic drug metformin. In low-density cultures of the C6 rat glioma cell line, metformin blocked the cell cycle progression in G0/G1 phase without inducing significant cell death. In confluent C6 cultures, on the other hand, metformin caused massive induction of caspase-dependent apoptosis associated with c-Jun N-terminal kinase (JNK) activation, mitochondrial depolarization and oxidative stress. Metformin-triggered apoptosis was completely prevented by agents that block mitochondrial permeability transition (cyclosporin A) and oxygen radical production (N-acetylcisteine), while the inhibitors of JNK activation (SP600125) or glycolysis (sodium fluoride, iodoacetate) provided partial protection. The antiglioma effect of metformin was reduced by compound C, an inhibitor of AMP-activated protein kinase (AMPK), and was mimicked by the AMPK agonist AICAR. Similar effects were observed in the human glioma cell line U251, while rat primary astrocytes were completely resistant to the antiproliferative and proapoptotic action of metformin.

Keywords.

Metformincancercell cycleapoptosismitochondrial depolarizationoxidative stressc-Jun N-terminal kinaseAMP-activated protein kinase

Copyright information

© Birkhäuser Verlag, Basel 2007

Authors and Affiliations

  • A. Isakovic
    • 1
  • L. Harhaji
    • 2
  • D. Stevanovic
    • 3
  • Z. Markovic
    • 4
  • M. Sumarac-Dumanovic
    • 5
  • V. Starcevic
    • 3
  • D. Micic
    • 5
  • V. Trajkovic
    • 6
  1. 1.Institute of Biochemistry, School of MedicineUniversity of BelgradeBelgradeSerbia
  2. 2.Institute for Biological ResearchBelgradeSerbia
  3. 3.Institute of Physiology, School of MedicineUniversity of BelgradeBelgradeSerbia
  4. 4.Vinca Institute of Nuclear SciencesBelgradeSerbia
  5. 5.Institute of Endocrinology, Diabetes and Diseases of Metabolism, School of MedicineUniversity of BelgradeBelgradeSerbia
  6. 6.Institute of Microbiology and Immunology, School of MedicineUniversity of BelgradeBelgradeSerbia