Co-administration of NVP-AEW541 and dasatinib induces mitochondrial-mediated apoptosis through Bax activation in malignant human glioma cell lines

Int J Oncol. 2010 Sep;37(3):633-43. doi: 10.3892/ijo_00000712.


Glioblastoma multiforme represents a largely incurable tumor for which novel therapeutic strategies are required. We report the effect of NVP-AEW541, an inhibitor of insulin-like growth factor-I receptor (IGF-IR) kinase activity on growth and signaling in a panel of glioma cell lines. NVP-AEW541 blocked phosphorylation of IGF-IR in a dose- and time-dependent manner and inhibited proliferation and clonogenicity with median effective concentrations of 2.5-10 microM. NVP-AEW541 also induced loss of mitochondrial membrane potential and release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria. Because concentrations of NVP-AEW541 required to significantly inhibit glioma cell viability and downstream signaling also inhibited non-neoplastic astrocytes, we questioned whether differential efficacy could be enhanced by combination with inhibition of other tyrosine kinases dysregulated in gliomas. Dasatinib was selected as a combination agent based on its distinct inhibitory profile for other relevant signaling targets. Combined treatment with NVP-AEW541 and dasatinib induced significantly more apoptosis than either agent alone in glioma cells, but not non-neoplastic astrocytes, and synergistically inhibited clonogenic survival. Mechanistic studies indicated that combination of NVP-AEW541 and dasatinib significantly reduced pERK and pAkt and markedly increased AIF release, Bax oligomerization and loss of mitochondrial potential compared to each agent alone. Overexpression of Bcl-2 and Akt significantly attenuated NVP-AEW541 and dasatinib-induced Bax activation and cell death. Our data indicate that activation of Bax plays a critical role in mediating NVP-AEW541 and dasatinib-induced apoptosis, and suggest the potential value of combining IGFR inhibition with other classes of tyrosine kinase inhibitors to potentiate therapeutic efficacy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Cell Cycle / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Dasatinib
  • Drug Synergism
  • Fluorescent Antibody Technique
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Mitochondria / drug effects*
  • Mitochondria / physiology
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology*
  • Pyrroles / administration & dosage
  • Pyrroles / pharmacology*
  • Signal Transduction / drug effects
  • Thiazoles / administration & dosage
  • Thiazoles / pharmacology*
  • Transfection
  • bcl-2-Associated X Protein / metabolism*


  • BAX protein, human
  • Cell Cycle Proteins
  • NVP-AEW541
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • Thiazoles
  • bcl-2-Associated X Protein
  • Dasatinib