Zhan L, Qin Q, Lu J, Liu J, Zhu H, Yang X, Zhang C, Xu L, Liu Z, Cai J, Ma J, Dai S, Tao G, Cheng H, Sun X
Department of Radiotherapy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Radiotherapy, Nantong Tumor Hospital Affiliated to Nantong University, Nantong, China.
Dis Esophagus. 2016 Apr;29(3):215-23. doi: 10.1111/dote.12299. Epub 2015 Jan 21.
Radiotherapy plays an important role in the treatment of esophageal squamous cell carcinoma (ESCC). However, the outcome of radiotherapy in ESCC remains unsatisfactory because esophageal squamous cancer cells, particularly those under hypoxic condition, exhibit radioresistance. The aim of this study was to determine whether or not AZD2281, a potent poly (ADP-ribose) polymerase (PARP) inhibitor, could enhance the radiation sensitivity of two ESCC cell lines, namely ECA109 and TE13. The radiosensitizing effect of AZD2281 was evaluated on the basis of cell death, clonogenic survival and tumor xenograft progression. AZD2281 alone was slightly toxic to ESCC cell lines. Apoptosis was increased and clonogenic survival was decreased in both cell lines when AZD2281 was combined with ionizing radiation (IR) under normoxic condition. AZD2281 enhanced IR-induced apoptosis to a more significant level under chronic hypoxic condition (0.2% O(2), 48 hour) than under normoxic condition. AZD2281 also slightly enhanced clonogenic cell death under chronic hypoxic condition compared with that under normoxic condition. This result could be associated with increased radiation-induced DNA double-strand breaks (DSB), decreased DSB repair and increased apoptosis of ESCC cells. Furthermore, homologous recombination (HR) protein Rad51 expression and focus formation were decreased in ESCC cells exposed to moderate chronic hypoxic condition (0.2% O(2), 48 hour); this result indicated that chronic hypoxic ESCC cells were HR deficient, possibly causing contextual synthetic lethality with PARP inhibitor in radiation sensitization. AZD2281 was also a radiation sensitizer in ESCC tumor xenograft models. Hence, in vitro and in vivo findings provide evidence that AZD2281 potently sensitizes ESCC cells to X-ray irradiation. The selective cell killing of HR-defective hypoxic cells contributes to radiosensitization by PARP inhibitor in ESCC cells under hypoxic condition.
放射治疗在食管鳞状细胞癌（ESCC）的治疗中起着重要作用。然而，ESCC的放射治疗效果仍不尽人意，因为食管鳞状癌细胞，尤其是在缺氧条件下的细胞，表现出放射抗性。本研究的目的是确定一种有效的聚（ADP - 核糖）聚合酶（PARP）抑制剂AZD2281是否能增强两种ESCC细胞系（即ECA109和TE13）的放射敏感性。基于细胞死亡、克隆形成存活和肿瘤异种移植进展来评估AZD2281的放射增敏作用。单独使用AZD2281对ESCC细胞系有轻微毒性。在常氧条件下，当AZD2281与电离辐射（IR）联合使用时，两种细胞系的凋亡增加，克隆形成存活减少。在慢性缺氧条件（0.2% O₂，48小时）下，AZD2281比在常氧条件下更显著地增强了IR诱导的凋亡。与常氧条件相比，AZD2281在慢性缺氧条件下也略微增强了克隆形成细胞死亡。这一结果可能与ESCC细胞中辐射诱导的DNA双链断裂（DSB）增加、DSB修复减少和凋亡增加有关。此外，在暴露于中度慢性缺氧条件（0.2% O₂，48小时）的ESCC细胞中，同源重组（HR）蛋白Rad51表达和灶形成减少；这一结果表明慢性缺氧的ESCC细胞存在HR缺陷，可能在放射增敏中与PARP抑制剂导致情境性合成致死。AZD2281在ESCC肿瘤异种移植模型中也是一种放射增敏剂。因此，体外和体内研究结果提供了证据，表明AZD2281能有效地使ESCC细胞对X射线照射敏感。HR缺陷的缺氧细胞的选择性细胞杀伤有助于PARP抑制剂在缺氧条件下对ESCC细胞的放射增敏作用。
