The DNA-PK Inhibitor VX-984 Enhances the Radiosensitivity of Glioblastoma Cells Grown In Vitro and as Orthotopic Xenografts.
The DNA-PK Inhibitor VX-984 Enhances the Radiosensitivity of Glioblastoma Cells Grown In Vitro and as Orthotopic Xenografts.
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DOI：
10.1158/1535-7163.mct-17-1267
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发表时间：
2018-06
影响因子：
5.7
通讯作者：
Tofilon PJ
中科院分区：
文献类型：
--
作者：
Timme CR;Rath BH;O'Neill JW;Camphausen K;Tofilon PJ
放射治疗是胶质母细胞瘤（GBM）的主要治疗方式。由于DNA-PKcs是辐射诱导双链断裂（DSB）修复的关键因素，本研究评估了新的DNA-PKcs抑制剂VX-984增强GBM细胞放射敏感性的潜力。体外条件下，VX-984处理已建立的GBM细胞系U251和GBM干细胞样细胞系NSC11，对辐射诱导的DNAPKcs磷酸化产生浓度依赖性抑制。以类似的浓度依赖性方式，VX-984处理增强了每个GBM细胞系的放射敏感性，这是由克隆源分析确定的。通过γ - h2ax表达和中性彗星分析，VX-984抑制了U251和NSC11 GBM细胞辐射诱导的DNA双链断裂的修复，表明VX-984诱导的辐射致敏是通过抑制DNA修复介导的。将这些结果扩展到体内模型，用VX-984治疗小鼠可以抑制放射诱导的原位脑肿瘤异种移植物中DNA-PKcs的磷酸化，表明该化合物以足够的浓度穿过血脑肿瘤屏障。对于患有U251或NSC11脑肿瘤的小鼠，单独使用VX-984治疗对总生存率无显著影响；单独放疗增加了生存率。与对照组和单独放疗相比，接受联合方案的小鼠的存活率显著增加。这些结果表明VX-984增强了异种脑瘤的放射敏感性，并提示它可能有益于GBM的治疗管理。
Radiotherapy is a primary treatment modality for glioblastomas (GBM). Because DNA-PKcs is a critical factor in the repair of radiation-induced double strand breaks (DSB), this study evaluated the potential of VX-984, a new DNA-PKcs inhibitor, to enhance the radiosensitivity of GBM cells. Treatment of the established GBM cell line U251 and the GBM stem-like cell (GSC) line NSC11 with VX-984 under in vitro conditions resulted in a concentration-dependent inhibition of radiation-induced DNAPKcs phosphorylation. In a similar concentration-dependent manner, VX-984 treatment enhanced the radiosensitivity of each GBM cell line as defined by clonogenic analysis. As determined by γH2AX expression and neutral comet analyses, VX-984 inhibited the repair of radiation-induced DNA double-strand break in U251 and NSC11 GBM cells, suggesting that the VX-984-induced radio-sensitization is mediated by an inhibition of DNA repair. Extending these results to an in vivo model, treatment of mice with VX-984 inhibited radiation-induced DNA-PKcs phosphorylation in orthotopic brain tumor xenografts, indicating that this compound crosses the blood–brain tumor barrier at sufficient concentrations. For mice bearing U251 or NSC11 brain tumors, VX-984 treatment alone had no significant effect on overall survival; radiation alone increased survival. The survival of mice receiving the combination protocol was significantly increased as compared with control and as compared with radiation alone. These results indicate that VX-984 enhances the radiosensitivity of brain tumor xenografts and suggest that it may be of benefit in the therapeutic management of GBM.