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.
Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Evaluation Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis / physiology
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Autophagy / drug effects
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Autophagy / physiology
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Benzenesulfonates / administration & dosage
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Benzenesulfonates / adverse effects
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Benzenesulfonates / pharmacology*
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Female
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Glioblastoma / drug therapy*
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Glioblastoma / metabolism
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Glioblastoma / pathology
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Glioma / drug therapy
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Glioma / metabolism
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Glioma / pathology
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Mice
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Mice, Nude
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Neoplasm Transplantation
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / pathology
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Niacinamide / analogs & derivatives
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Phenylurea Compounds
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Protein Kinase Inhibitors / pharmacology
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Pyridines / administration & dosage
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Pyridines / adverse effects
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Pyridines / pharmacology*
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Random Allocation
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Sorafenib
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Treatment Outcome
Substances
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Antineoplastic Agents
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Benzenesulfonates
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Phenylurea Compounds
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Protein Kinase Inhibitors
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Pyridines
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Niacinamide
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Sorafenib