Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Cancer Res. 2010 Nov 1;70(21):8684-94. doi: 10.1158/0008-5472.CAN-10-2227. Epub 2010 Sep 13.
Previous studies have shown that telomerase facilitates DNA-damage repair and cell survival following stress. It is not clear how telomerase promotes DNA repair, or whether short-term telomerase inhibition, combined with genotoxic stress, can be exploited for cancer therapy. Here, we show that transient inhibition of telomerase activity by the specific inhibitor, GRN163L, increases the cytotoxicity of some, but not all, DNA-damaging agents. Such synergistic inhibition of growth requires the use of DNA-damaging agents that are toxic in the S/G(2) phase of the cell cycle. Notably, inhibition of Ataxia Telangiectasia Mutated (ATM) kinase, together with telomerase inhibition, synergistically increases the cytotoxicity induced by the G(2)-specific topoisomerase II inhibitor etoposide. By varying the timing of telomerase inhibition, relative to the timing of DNA damage, it is apparent that the prosurvival functions of telomerase occur at early stages of DNA damage recognition and repair. Our results suggest that the protective role of telomerase in cell cycle-restricted DNA damage repair could be exploited for combined anticancer chemotherapy.
先前的研究表明，端粒酶有助于在应激后修复 DNA 损伤并促进细胞存活。目前尚不清楚端粒酶如何促进 DNA 修复，也不清楚短期抑制端粒酶活性，结合遗传毒性应激，是否可用于癌症治疗。在此，我们发现通过特异性抑制剂 GRN163L 短暂抑制端粒酶活性可增加某些而非所有 DNA 损伤剂的细胞毒性。这种协同的生长抑制作用需要使用在细胞周期 S/G2 期有毒性的 DNA 损伤剂。值得注意的是，与端粒酶抑制作用相结合，抑制共济失调毛细血管扩张突变（ATM）激酶可协同增加 G2 期拓扑异构酶 II 抑制剂依托泊苷诱导的细胞毒性。通过改变端粒酶抑制相对于 DNA 损伤的时间，可以明显看出端粒酶的生存促进功能发生在 DNA 损伤识别和修复的早期阶段。我们的研究结果表明，端粒酶在细胞周期受限的 DNA 损伤修复中的保护作用可用于联合抗癌化疗。
