PARP inhibitor olaparib sensitizes esophageal carcinoma cells to fractionated proton irradiation
PARP inhibitor olaparib sensitizes esophageal carcinoma cells to fractionated proton irradiation
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DOI：
10.1093/jrr/rrz088
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发表时间：
2020-03-01
影响因子：
2
通讯作者：
Akimoto, Tetsuo
中科院分区：
文献类型：
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作者：
Kageyama, Shun-ichiro;Junyan, Du;Akimoto, Tetsuo
质子束治疗（PBT）联合化疗，如顺式二胺二氯铂（CDDP）和5-氟尿嘧啶（5-FU），已被用作改善临床结果的替代方法。据报道，PBT对食管癌有效。然而，除了5-FU和CDDP外，几乎没有其他药物在PBT联合化疗中进行过试验。因此，我们研究了一种聚（adp -核糖）聚合酶抑制剂对食管癌细胞系增强质子束效应的影响，这些食管癌细胞系表现出辐射和CDDP抗性。食管鳞状细胞癌细胞OE-21和KYSE-450在辐照前暴露于药物1小时。用克隆实验获得细胞存活曲线，计算致敏效应比（SER）。采用克隆实验比较8 Gy/1分次（fr）和8 Gy/4次（fr）多分次辐照的效果。免疫荧光法检测γ - H2AX、Rad51、BRCA1、BRCA2和53BP1灶。奥拉帕尼在PBT上的SER为1.5-1.7。多次分次照射也有相同的增敏效果，并且联合使用以加性方式增加了双链断裂和同源重组相关基因的表达。在非同源末端连接相关基因中未观察到这种加性效应。我们证明了奥拉帕尼对铂耐药和耐辐射食管癌细胞中的PBT具有高度的增敏作用。我们的结果提示奥拉帕尼质子照射（PT）治疗铂耐药和辐射耐药食管癌的潜在临床应用。
Proton beam therapy (PBT) combined with chemotherapy, such as cis-diamminedichloroplatinum (II) (CDDP) and 5-fluorouracil (5-FU), has been employed as an alternative approach to improve clinical outcomes. PBT has been reported to be effective against esophageal cancer. However, apart from 5-FU and CDDP, almost no other drug has been tested in combined chemotherapy with PBT. Therefore, we investigated the effects of a poly (ADP-ribose) polymerase inhibitor on enhancing proton beam effects using esophageal cancer cell lines that exhibit resistance to radiation and CDDP. Esophageal squamous cell carcinoma cell lines OE-21 and KYSE-450 were exposed to the drugs for 1 h prior to irradiation. The cell survival curve was obtained using a clonogenic assay and the sensitizing effect ratio (SER) was calculated. The clonogenic assay was used to compare the effect of multi-fractioned irradiation between 8 Gy/1 fraction (fr) and 8 Gy/4 fr. gamma H2AX, Rad51, BRCA1, BRCA2 and 53BP1 foci were detected via immunofluorescence. Olaparib exhibited an SER of 1.5-1.7 on PBT. The same sensitizing effect was exhibited in multi-fractioned irradiation, and the combined use increased the expression of double-strand breaks and homologous recombination-related genes in an additive manner. Such additive effects were not observed on non-homologous end joining-related genes. We demonstrated that olaparib has a high sensitizing effect on PBT in platinum- and radiation-resistant esophageal cancer cells. Our results suggest a potential clinical application of olaparib-proton irradiation (PT) against platinum- and radiation-resistant esophageal cancer.