title: Cytotoxic and radiosensitizing effects of FAK targeting in human glioblastoma cells in vitro.
abstract: Glioblastoma multiforme (GBM) is a highly aggressive and extremely lethal cancer and novel molecular therapies are required for optimized multimodal therapy regimes. While focal adhesion kinase (FAK) is regarded as a therapeutic target, its radiosensitizing potential remains to be elucidated in glioblastoma. Thus, FAK was inhibited using the pharmaco-logical inhibitor TAE226 and cytotoxicity and radiosensitization of glioblastoma cells were investigated in vitro. Monolayer and suspension cell cultures of a panel of glioblastoma cell lines (A172, LN229, U87MG, U138MG, U343MG, DD-HT7607, and DD-T4) were treated with increasing TAE226 concentrations (0-10 µM) alone or in combination with X-rays (0-6 Gy). Subsequently, clonogenic cell survival, expression and the phosphorylation of FAK downstream signaling, apoptosis and autophagy were analyzed. Efficient FAK inhibition by TAE226 mediated significant cytotoxicity and reduced sphere formation in a dose- and time-dependent manner. Two out of seven glioblastoma cell lines showed radiosensitization. Apoptotic induction by TAE226 was cell line-dependent. The results demonstrated that pharmacological FAK inhibitor TAE226 efficiently reduced clonogenicity and sphere formation in glioblastoma cells without generally modifying their radiosensitivity. However, future studies are necessary to define the potential of FAK inhibition by TAE226 or other pharmacological inhibitors in combination with radiochemotherapy.
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, and Helmholtz-Zentrum Dresden - Rossendorf, D-01307 Dresden, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Storch
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, and Helmholtz-Zentrum Dresden - Rossendorf, D-01307 Dresden, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Sagerer
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, and Helmholtz-Zentrum Dresden - Rossendorf, D-01307 Dresden, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Cordes
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D009025:Morpholines; D011838:Radiation-Sensitizing Agents; C524632:TAE226; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human