Wu Xuping, Zhang Jing, Yang Sijun, Kuang Zhihui, Tan Guolei, Yang Gang, Wei Qichun, Guo Zhigang
The Second Hospital of Nanjing Affiliated to Medical School of Southeast University, Nanjing 210003, China.
Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China.
Oncotarget. 2017 Feb 21;8(8):13600-13619. doi: 10.18632/oncotarget.14618.
The morbidity and mortality of esophageal cancer is one of the highest around the world and the principal therapeutic method is radiation. Thus, searching for sensitizers with lower toxicity and higher efficiency to improve the efficacy of radiation therapy is critical essential. Our research group has previously reported that imetelstat, the thio-phosphoramidate oligonucleotide inhibitor of telomerase, can decrease cell proliferation and colony formation ability as well as increase DNA breaks induced by radiation in esophageal cancer cells. Further study in this project showed that imetelstat significantly sensitized esophageal cancer cells to radiation in vitro. Later study showed that imetelstat leads to increased cell apoptosis. We also measured the expression level of several DNA repair and apoptosis signaling proteins. pS345 CHK1, γ-H2AX, p53 and caspase3 expression were up-regulated in imetelstat treated cells, identifying these factors as molecular markers. Mouse in vivo model using imetelstat at clinically achievable concentrations and fractionated irradiation scheme yielded results demonstrating radiosensitization effect. Finally, TUNEL assay, caspase 3 and Ki67 staining in tumor tissue proved that imetelstat sensitized esophageal cancer to radiation in vivo through promoting cell apoptosis and inhibiting cell proliferation. Our study supported imetelstat increase radiation sensitivity of esophageal squamous cell carcinoma through inducing cell apoptosis and the specific inhibitor of telomerase might serve as a potential novel therapeutic tool for esophageal squamous cell carcinoma therapy.
食管癌的发病率和死亡率在全球范围内位居前列，主要治疗方法是放疗。因此，寻找毒性更低、效率更高的增敏剂以提高放疗疗效至关重要。我们的研究小组之前报道过，端粒酶硫代磷酰胺寡核苷酸抑制剂艾美拉唑可降低食管癌细胞的增殖和集落形成能力，并增加放疗诱导的DNA断裂。该项目的进一步研究表明，艾美拉唑在体外可显著使食管癌细胞对放疗敏感。后续研究表明，艾美拉唑可导致细胞凋亡增加。我们还检测了几种DNA修复和凋亡信号蛋白的表达水平。在经艾美拉唑处理的细胞中，pS345 CHK1、γ-H2AX、p53和caspase3表达上调，确定这些因子为分子标志物。使用临床可达到浓度的艾美拉唑和分次照射方案的小鼠体内模型产生的结果证明了放射增敏作用。最后，肿瘤组织中的TUNEL检测、caspase 3和Ki67染色证明，艾美拉唑通过促进细胞凋亡和抑制细胞增殖使食管癌在体内对放疗敏感。我们的研究支持艾美拉唑通过诱导细胞凋亡增加食管鳞状细胞癌的放射敏感性，端粒酶的特异性抑制剂可能成为食管鳞状细胞癌治疗的一种潜在新型治疗工具。
