title: Sunitinib targets PDGF-receptor and Flt3 and reduces survival and migration of human meningioma cells.
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 5 μM sunitinib, with IC(50) values between 2 and 5 μM in all cell lines. This effect was associated with a G(2)M-arrest at 10 μM for BenMen-1, HBL52 and IOMM-Lee, and 20 μM in KT21MG cells. Nuclear bisbenzimide staining revealed chromatin condensation following treatment with sunitinib concentrations of 10 μM 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 IC(50)-values between 10 and 20 μM. However, pre-irradiated meningioma cells (5 Gy) showed a sensitivity shift towards IC(50)-values around 5 μM sunitinib. We also found that 5 μM 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.
authors.affiliation: Department of Neuropathology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Andrae
authors.forename: Elmar
authors.initials: E
authors.lastname: Kirches
authors.forename: Roland
authors.initials: R
authors.lastname: Hartig
authors.forename: Daniela
authors.initials: D
authors.lastname: Haase
authors.forename: Gerburg
authors.initials: G
authors.lastname: Keilhoff
authors.forename: Thomas
authors.initials: T
authors.lastname: Kalinski
authors.forename: Christian
authors.initials: C
authors.lastname: Mawrin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008577:Meningeal Neoplasms / Q000188:drug therapy*; D008579:Meningioma / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D000077210:Sunitinib; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D004247:DNA; D017479:Receptors, Platelet-Derived Growth Factor; D051941:fms-Like Tyrosine Kinase 3; D000077210:Sunitinib