title: A combination of tyrosine kinase inhibitors, crizotinib and dasatinib for the treatment of glioblastoma multiforme.
abstract: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Despite the advances in surgery, radiotherapy and chemotherapy, patient survival averages only 14.6 months. In most GBM tumors, tyrosine kinases show increased activity and/or expression and actively contribute to the development, recurrence and onset of treatment resistance; making their inhibition an appealing therapeutic strategy. We compared the cytotoxicity of 12 tyrosine kinase inhibitors in vitro. A combination of crizotinib and dasatinib emerged as the most cytotoxic across established and primary human GBM cell lines. The combination treatment induced apoptotic cell death and polyploidy. Furthermore, the combination treatment led to the altered expression and localization of several tyrosine kinase receptors such as Met and EGFR and downstream effectors as such as SRC. Furthermore, the combination treatment reduced the migration and invasion of GBM cells and prevented endothelial cell tube formation in vitro. Overall, our study demonstrated the broad specificity of a combination of crizotinib and dasatinib across multiple GBM cell lines. These findings provide insight into the development of alternative therapy for the treatment of GBM.
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
authors.forename: Hayley
authors.initials: H
authors.lastname: Nehoff
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
authors.forename: Neha N
authors.initials: NN
authors.lastname: Parayath
authors.affiliation: School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: McConnell
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Taurin
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
authors.forename: Khaled
authors.initials: K
authors.lastname: Greish
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D000069439:Dasatinib / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D019084:Fluorescent Antibody Technique, Indirect; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D008941:Spindle Apparatus / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D000069439:Dasatinib
keywords: Met; SRC; glioblastoma multiforme; invasion; tyrosine kinase inhibitors