Wu Xuping, Smavadati Shirin, Nordfjäll Katarina, Karlsson Krister, Qvarnström Fredrik, Simonsson Martin, Bergqvist Michael, Gryaznov Sergei, Ekman Simon, Paulsson-Karlsson Ylva
Department of Radiology, Oncology and Radiation Sciences, Section of Oncology, Uppsala University, Sweden.
Biochim Biophys Acta. 2012 Dec;1823(12):2130-5. doi: 10.1016/j.bbamcr.2012.08.003. Epub 2012 Aug 11.
Telomerase is mainly active in human tumor cells, which provides an opportunity for a therapeutic window on telomerase targeting. We sought to evaluate the potential of the thio-phosphoramidate oligonucleotide inhibitor of telomerase, imetelstat, as a drug candidate for treatment of esophageal cancer. Our results showed that imetelstat inhibited telomerase activity in a dose-dependent manner in esophageal cancer cells. After only 1 week of imetelstat treatment, a reduction of colony formation ability of esophageal cancer cells was observed. Furthermore, long-term treatment with imetelstat decreased cell growth of esophageal cancer cells with different kinetics regarding telomere lengths. Short-term imetelstat treatment also increased γ-H2AX and 53BP1 foci staining in the esophageal cancer cell lines indicating a possible induction of DNA double strand breaks (DSBs). We also found that pre-treatment with imetelstat led to increased number and size of 53BP1 foci after ionizing radiation. The increase of 53BP1 foci number was especially pronounced during the first 1h of repair whereas the increase of foci size was prominent later on. This study supports the potential of imetelstat as a therapeutic agent for the treatment of esophageal cancer.
端粒酶主要在人类肿瘤细胞中具有活性，这为以端粒酶为靶点的治疗提供了机会。我们试图评估端粒酶的硫代磷酰胺寡核苷酸抑制剂艾美拉唑作为治疗食管癌的候选药物的潜力。我们的结果表明，艾美拉唑在食管癌细胞中以剂量依赖的方式抑制端粒酶活性。仅用艾美拉唑治疗1周后，就观察到食管癌细胞集落形成能力下降。此外，长期使用艾美拉唑可降低不同端粒长度动力学的食管癌细胞的生长。短期艾美拉唑治疗还增加了食管癌细胞系中γ-H2AX和53BP1焦点染色，表明可能诱导了DNA双链断裂（DSB）。我们还发现，用艾美拉唑预处理导致电离辐射后53BP1焦点的数量和大小增加。53BP1焦点数量的增加在修复的最初1小时尤为明显，而焦点大小的增加在后期更为突出。这项研究支持了艾美拉唑作为治疗食管癌的治疗剂的潜力。
