Corresponding Author: Randy Y.C. Poon, Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
Mol Cancer Ther. 2013 Nov;12(11):2517-28. doi: 10.1158/1535-7163.MCT-13-0010. Epub 2013 Aug 26.
Nasopharyngeal carcinoma is a rare but highly invasive cancer. As options of agents for effective combination chemoradiotherapy for advanced nasopharyngeal carcinoma are limited, novel therapeutic approaches are desperately needed. The ubiquitin ligase CHFR is known to target PARP1 for degradation and is epigenetically inactivated in nasopharyngeal carcinoma. We present evidence that PARP1 protein is indeed overexpressed in nasopharyngeal carcinoma cells in comparison with immortalized normal nasopharyngeal epithelial cells. Tissue microarray analysis also indicated that PARP1 protein is significantly elevated in primary nasopharyngeal carcinoma tissues, with strong correlation with all stages of nasopharyngeal carcinoma development. We found that the PARP inhibitor AZD2281 (olaparib) increased DNA damage, cell-cycle arrest, and apoptosis in nasopharyngeal carcinoma cells challenged with ionizing radiation or temozolomide. Isobologram analysis confirmed that the cytotoxicity triggered by AZD2281 and DNA-damaging agents was synergistic. Finally, AZD2281 also enhanced the tumor-inhibitory effects of ionizing radiation in animal xenograft models. These observations implicate that PARP1 overexpression is an early event in nasopharyngeal carcinoma development and provide a molecular basis of using PARP inhibitors to potentiate treatment of nasopharyngeal carcinoma with radio- and chemotherapy.
鼻咽癌是一种罕见但具有高度侵袭性的癌症。由于有效的晚期鼻咽癌联合放化疗药物选择有限，因此迫切需要新的治疗方法。已知泛素连接酶 CHFR 通过降解 PARP1 来靶向 PARP1，并且在鼻咽癌中被表观遗传失活。我们提供的证据表明，与永生化的正常鼻咽上皮细胞相比，PARP1 蛋白在鼻咽癌细胞中确实过表达。组织微阵列分析还表明，PARP1 蛋白在原发性鼻咽癌组织中显著升高，与鼻咽癌发展的所有阶段均具有强相关性。我们发现，PARP 抑制剂 AZD2281（奥拉帕利）增加了电离辐射或替莫唑胺处理的鼻咽癌细胞中的 DNA 损伤、细胞周期停滞和细胞凋亡。等效应线分析证实，AZD2281 和 DNA 损伤药物引发的细胞毒性具有协同作用。最后，AZD2281 还增强了放射性和化学疗法在动物异种移植模型中的肿瘤抑制作用。这些观察结果表明，PARP1 过表达是鼻咽癌发生的早期事件，并为使用 PARP 抑制剂增强鼻咽癌的放射和化学治疗提供了分子基础。
