Sensitization of chondrosarcoma cells with PARP inhibitor and high-LET radiation
Sensitization of chondrosarcoma cells with PARP inhibitor and high-LET radiation
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DOI：
10.1016/j.jbo.2019.100246
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发表时间：
2019-08-01
影响因子：
3.4
通讯作者：
Chevalier, Francois
中科院分区：
文献类型：
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作者：
Cesaire, Mathieu;Ghosh, Utpal;Chevalier, Francois
软骨肉瘤是一种恶性肿瘤，它起源于软骨组织，对常规治疗具有放射抗性和化学抗性。首选的治疗方法包括手术切除，这可能会导致患者严重残疾;此外，对于不可手术的位置，如颅底，这种手术可能是不可能的。碳离子辐射（强子疗法）已被提出作为一种替代治疗，主要是由于其更大的生物学效果和改善弹道性能相比，传统的放射治疗与X射线。本研究的目的是表征III级软骨肉瘤细胞系（CH 2879）的基因突变，并检查在PARP抑制剂奥拉帕尼存在下对常规放疗（X射线）和强子疗法（质子和碳离子）的细胞反应。为了更好地理解PARP抑制，我们首先通过蛋白质印迹分析了聚ADP核糖链的形成;我们观察到照射后其信号增加，在添加PARP抑制剂后消失。PARPi分别用X射线、质子和C-离子照射细胞后，如通过克隆形成测定所检测到的，PARPi增强了约1.3、1.8和1.5的比率。通过增殖测定证实细胞存活率的降低。CH 2879细胞的放射敏感性与同源重组修复基因如RAD 50、SMARCA 2和NBN的突变有关。本研究证明了PARP抑制剂奥拉帕尼对突变软骨肉瘤细胞进行常规光子照射、质子和碳离子照射的放射增敏能力。
Chondrosarcoma is a malignant tumor that arises from cartilaginous tissue and is radioresistant and chemoresistant to conventional treatments. The preferred treatment consists of surgical resection, which might cause severe disabilities for the patient; in addition, this procedure might be impossible for inoperable locations, such as the skull base. Carbon ion irradiation (hadron therapy) has been proposed as an alternative treatment, primarily due to its greater biological effectiveness and improved ballistic properties compared with conventional radiotherapy with X-rays. The goal of this study was to characterize the genetic mutations of a grade III chondrosarcoma cell line (CH2879) and examine the cellular responses to conventional radiotherapy (X-rays) and hadron therapy (proton and carbon ions) in the presence of the PARP inhibitor Olaparib. To better understand PARP inhibition, we first analyzed the formation of poly-ADP ribose chains by western blot; we observed an increase in its signal after irradiation, which disappeared on addition of the PARP inhibitor. PARPi enhanced ratio of approximately 1.3, 1.8, and 1.5 following irradiation of cells with X-rays, protons, and C-ions, respectively, as detected by clonogenic assay. The decrease in cell survival was confirmed by proliferation assay. The radiosensitivity of CH2879 cells was associated with mutations in homologous recombination repair genes, such as RAD50, SMARCA2 and NBN. This study demonstrates the capacity of the PARP inhibitor Olaparib to radiosensitize mutated chondrosarcoma cells to conventional photon irradiation, proton and carbon ion irradiation.