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

  • Authors:
    • Daniel R. Premkumar
    • Esther P. Jane
    • Ian F. Pollack
  • View Affiliations

  • Published online on: September 1, 2010     https://doi.org/10.3892/ijo_00000712
  • Pages: 633-643
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

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 µM. 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.

Related Articles

Journal Cover

September 2010
Volume 37 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Premkumar DR, Jane EP and Pollack IF: Co-administration of NVP-AEW541 and dasatinib induces mitochondrial-mediated apoptosis through Bax activation in malignant human glioma cell lines. Int J Oncol 37: 633-643, 2010.
APA
Premkumar, D.R., Jane, E.P., & Pollack, I.F. (2010). Co-administration of NVP-AEW541 and dasatinib induces mitochondrial-mediated apoptosis through Bax activation in malignant human glioma cell lines. International Journal of Oncology, 37, 633-643. https://doi.org/10.3892/ijo_00000712
MLA
Premkumar, D. R., Jane, E. P., Pollack, I. F."Co-administration of NVP-AEW541 and dasatinib induces mitochondrial-mediated apoptosis through Bax activation in malignant human glioma cell lines". International Journal of Oncology 37.3 (2010): 633-643.
Chicago
Premkumar, D. R., Jane, E. P., Pollack, I. F."Co-administration of NVP-AEW541 and dasatinib induces mitochondrial-mediated apoptosis through Bax activation in malignant human glioma cell lines". International Journal of Oncology 37, no. 3 (2010): 633-643. https://doi.org/10.3892/ijo_00000712