Nehoff Hayley, Parayath Neha N, McConnell Melanie J, Taurin Sebastien, Greish Khaled
Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand.
School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
Oncotarget. 2015 Nov 10;6(35):37948-64. doi: 10.18632/oncotarget.5698.
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.
多形性胶质母细胞瘤（GBM）是最常见且侵袭性最强的原发性脑肿瘤。尽管在手术、放疗和化疗方面取得了进展，但患者的平均生存期仅为14.6个月。在大多数GBM肿瘤中，酪氨酸激酶的活性和/或表达增加，并积极促进肿瘤的发展、复发和治疗耐药性的产生；因此抑制酪氨酸激酶成为一种有吸引力的治疗策略。我们在体外比较了12种酪氨酸激酶抑制剂的细胞毒性。在已建立的和原代人GBM细胞系中，克唑替尼和达沙替尼的组合表现出最强的细胞毒性。联合治疗诱导了凋亡性细胞死亡和多倍体形成。此外，联合治疗导致了几种酪氨酸激酶受体（如Met和EGFR）以及下游效应分子（如SRC）的表达和定位发生改变。此外，联合治疗降低了GBM细胞的迁移和侵袭能力，并在体外阻止了内皮细胞管的形成。总体而言，我们的研究证明了克唑替尼和达沙替尼组合对多种GBM细胞系具有广泛的特异性。这些发现为GBM治疗的替代疗法的开发提供了思路。
