Abstract
The multitargeted tyrosine-kinase inhibitor sunitinib is a highly effective anti-angiogenic and cytostatic agent in the therapy of various tumours. While malignant gliomas have been shown to be responsive to sunitinib, detailed studies analysing human meningiomas are missing. We therefore analysed the effects of sunitinib in two benign (BenMen-1, HBL52) and two malignant (IOMM-Lee, KT21MG) human meningioma cell lines and found that DNA synthesis was significantly (p⩽0.001) inhibited following 1, 2 or 5μM sunitinib, with IC50 values between 2 and 5μM in all cell lines. This effect was associated with a G2M-arrest at 10μM for BenMen-1, HBL52 and IOMM-Lee, and 20μM in KT21MG cells. Nuclear bisbenzimide staining revealed chromatin condensation following treatment with sunitinib concentrations of 10μM or higher. Corresponding, cell viability assays showed a significant (p⩽0.001) short term decrease of viable cells (24h) only for high sunitinib concentrations with IC50-values between 10 and 20μM. However, pre-irradiated meningioma cells (5Gy) showed a sensitivity shift towards IC50-values around 5μM sunitinib. We also found that 5μM strongly reduced meningioma cell migration in vitro. Western blot analyses showed abolished platelet derived growth factor receptor (PDGFR)-autophosphorylation after sunitinib. Interestingly, the drug also inhibited the autophosphorylation of the receptor tyrosine kinase fms-like tyrosine kinase 3 (Flt3) in a dose-dependent manner. Taken together, the present data show that micromolar sunitinib has strong cytostatic and anti-migratory effects on human meningioma cells.
Published Version
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