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Coadministration of NVP-AEW541 and Dasatinib induces mitochondrial-mediated apoptosis through Bax activation in Malignant Human Glioma Cell Lines

Premkumar, Daniel R and Jane, Esther P and Pollack, Ian F and Imark, Esther (2010) Coadministration of NVP-AEW541 and Dasatinib induces mitochondrial-mediated apoptosis through Bax activation in Malignant Human Glioma Cell Lines. International Journal of Oncology, 37 (3). pp. 633-643. ISSN 1019-6439

Abstract

Despite recent advances in treatment, glioblastoma multiforme (GBM) represents an incurable disease for which development of new therapies is required. We report the effect of NVP-AEW541, a small molecule inhibitor of insulin-like growth factor-I receptor (IGF-IR) kinase activity on growth and signaling in a panel of glioma cell lines. NVPAEW541 blocked phosphorylation of IGF-IR in a dose- and time-dependent manner and inhibited proliferation and clonogenicity with median effective concentrations (IC50) in the range of 2.5 to 10 µM. NVPAEW541 also induced loss of mitochondrial membrane potential and release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria. However, the concentrations of NVP-AEW541 required to significantly inhibit glioma cell viability and downstream signaling also had some inhibitory activity on non-neoplastic astrocytes, which led us to question whether therapeutic efficacy could be enhanced by combination of lower concentrations of NVP-AEW541 with inhibition of other tyrosine kinases dysregulated in gliomas. Dasatinib was selected as a combination agent based on its distinct profile of inhibiting other relevant signaling targets in gliomas, including EGFR and PDGFR. Combined treatment of glioma cells with NVP-AEW541 and dasatinib induced significantly more apoptosis than either agent alone in glioma cells, but not non-neoplastic astrocytes, as well as synergistically inhibiting clonogenic survival. Mechanistic studies indicated that the combination of NVP-AEW541 and dasatinib resulted in a significant reduction of pERK and pAkt and provoked a marked increase in AIF release to the nucleus, Bax oligomerization and loss of mitochondrial potential compared to each agent alone. Overexpression of BCL-2 and Akt significantly attenuated NVP-AEW541 and dasatinib-Bax activation and cell death. Our data indicate that activation of BAX plays a critical role in mediating NVP-AEW541 and dasatinib-induced apoptotic cascades. These data suggest the potential value of combining IGFR inhibition with other classes of tyrosine kinase inhibitors as a way to potentiate therapeutic efficacy.

Item Type: Article
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Additional Information: No publisher information available on SHERPA nor the publishers website.
Keywords: Glioblastoma multiforme; NVP-AEW541
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/1603

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