Pharmacologic blockade of FAK autophosphorylation decreases human glioblastoma tumor growth and synergizes with temozolomide.
Pharmacologic blockade of FAK autophosphorylation decreases human glioblastoma tumor growth and synergizes with temozolomide.
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DOI：
10.1158/1535-7163.mct-12-0701
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发表时间：
2013-02
影响因子：
5.7
通讯作者：
Cance WG
中科院分区：
文献类型：
--
作者：
Golubovskaya VM;Huang G;Ho B;Yemma M;Morrison CD;Lee J;Eliceiri BP;Cance WG
恶性神经胶质瘤的特征是侵袭性肿瘤生长，平均生存期为15-18个月，并且经常对替莫唑胺产生耐药性。因此，使神经胶质瘤细胞对替莫唑胺敏感的策略具有高的翻译影响。我们已经研究了粘着斑激酶（FAK），一种酪氨酸激酶和新兴的治疗靶点，已知在胶质瘤中高度表达和激活。在这份报告中，我们测试了FAK自磷酸化抑制剂，Y15在DBTRG和U87胶质母细胞瘤细胞。Y15以剂量依赖性方式显着降低活力和克隆形成，以剂量和时间依赖性方式增加脱落，引起细胞凋亡并抑制两种细胞系的细胞侵袭。此外，Y15处理以剂量依赖性方式减少FAK的自磷酸化，并通过引起DBTRG和U87细胞中的细胞变圆而改变细胞形态。施用Y15显著降低皮下DBTRG肿瘤生长，降低Y397-FAK自磷酸化，活化半胱天冬酶-3和PARP。在原位神经胶质瘤模型中施用Y15，导致小鼠存活率增加。Y15与替莫唑胺的组合在体外降低DBTRG和U87细胞中的存活率和激活半胱天冬酶-8方面比任一单独药剂更有效。此外，Y15和替莫唑胺的组合在体内协同阻断U87脑肿瘤生长。因此，通过口服小分子抑制剂Y15对FAK自磷酸化进行药理学阻断有可能成为胶质母细胞瘤的有效治疗方法，无论是单独使用还是与化疗药物如替莫唑胺联合使用。
Malignant gliomas are characterized by aggressive tumor growth with a mean survival of 15–18 months and frequently developed resistance to temozolomide. Therefore, strategies that sensitize glioma cells to temozolomide have a high translational impact. We have studied focal adhesion kinase (FAK), a tyrosine kinase and emerging therapeutic target that is known to be highly expressed and activated in glioma. In this report we tested the FAK autophosphorylation inhibitor, Y15 in DBTRG and U87 glioblastoma cells. Y15 significantly decreased viability and clonogenicity in a dose-dependent manner, increased detachment in a dose and time-dependent manner, caused apoptosis and inhibited cell invasion in both cell lines. In addition, Y15 treatment decreased autophosphorylation of FAK in a dose-dependent manner and changed cell morphology by causing cell rounding in DBTRG and U87 cells. Administration of Y15 significantly decreased subcutaneous DBTRG tumor growth with decreased Y397-FAK autophosphorylation, activated caspase-3 and PARP. Y15 was administered in an orthotopic glioma model, leading to an increase in mouse survival. The combination of Y15 with temozolomide was more effective than either agent alone in decreasing viability and activating caspase-8 in DBTRG and U87 cells in vitro. In addition, the combination of Y15 and temozolomide synergistically blocked U87 brain tumor growth in vivo. Thus, pharmacologic blockade of FAK autophosphorylation with the oral administration of a small molecule inhibitor Y15 has a potential to be an effective therapy approach for glioblastoma either alone or in combination with chemotherapy agents such as temozolomide.