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Sorafenib exerts anti-glioma activity in vitro and in vivo
Markus D Siegelin1, Christopher M Raskett, Candace A Gilbert
1Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. msiegelin@t-online.de
Abstract:
Despite conventional treatment strategies glioblastoma, the most common malignant primary brain tumor, has a bad prognosis with median survival times of 12-15 months. In this study, the efficacy of sorafenib (Nexavar, BAY43-9006), a multikinase inhibitor, on glioblastoma cells was evaluated both in vitro and in vivo. Treatment of established or patient-derived glioblastoma cells with low concentrations of sorafenib caused a dramatic dose dependent inhibition of proliferation (IC(50), 1.5 microM) and induction of apoptosis and autophagy. Sorafenib inhibited phosphorylation of signal transducer and activator of transcription 3 (Stat3) and expression of cyclins, D and E. In contrast, AKT was not modulated by sorafenib. Most important, systemic delivery of sorafenib was well tolerated, and significantly suppressed intracranial glioma growth via inhibition of cell proliferation, induction of apoptosis and autophagy, and reduction of angiogenesis. Furthermore, intracranial growth inhibition by sorafenib was accompanied by a significant reduction in ph-Stat3 (Tyr 705) levels. In summary, sorafenib has potent anti-glioma activity in vitro and in vivo.
Insights
Sorafenib, a multikinase inhibitor, effectively combats glioblastoma by inhibiting proliferation and inducing cell death. This drug shows potent anti-glioma activity in vitro and in vivo, offering a promising therapeutic avenue.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Glioblastoma is an aggressive brain tumor with poor prognosis despite current treatments.
- Novel therapeutic strategies are urgently needed to improve patient outcomes.
Purpose of the Study:
- To evaluate the efficacy of sorafenib, a multikinase inhibitor, against glioblastoma.
- To investigate the molecular mechanisms underlying sorafenib's action in glioblastoma cells.
Main Methods:
- In vitro studies using established and patient-derived glioblastoma cells.
- In vivo studies involving systemic delivery of sorafenib in a glioma model.
- Analysis of cell proliferation, apoptosis, autophagy, and key signaling pathways (Stat3, AKT).
Main Results:
- Sorafenib demonstrated dose-dependent inhibition of glioblastoma cell proliferation (IC50 = 1.5 microM) and induced apoptosis and autophagy.
- Sorafenib suppressed phosphorylation of signal transducer and activator of transcription 3 (Stat3) and reduced cyclin D and E expression.
- Systemic sorafenib treatment was well-tolerated, suppressed intracranial glioma growth, and reduced angiogenesis, correlating with decreased p-Stat3 levels.
Conclusions:
- Sorafenib exhibits potent anti-glioma activity in both in vitro and in vivo models.
- Sorafenib's efficacy is mediated through inhibition of proliferation, induction of apoptosis and autophagy, and modulation of Stat3 signaling.
- Sorafenib represents a promising therapeutic agent for glioblastoma treatment.
