Increasing sensitivity to arsenic trioxide-induced apoptosis by altered telomere state.
Increasing sensitivity to arsenic trioxide-induced apoptosis by altered telomere state.
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DOI：
10.1016/s0014-2999(03)02013-2
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发表时间：
2003-08
影响因子：
5
通讯作者：
Yan Zhang;E. Cao;Xiao-Qiu Liang;J. Qin
中科院分区：
文献类型：
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作者：
Yan Zhang;E. Cao;Xiao-Qiu Liang;J. Qin
在这项工作中，我们研究了低剂量三氧化二砷和二乙基氧杂二氮杂双环菁（DODC），端粒酶抑制剂，对细胞凋亡的协同作用。结果表明，低剂量砷可使细胞周期阻滞于G2/M期，并诱导细胞凋亡，而DODC可使细胞周期阻滞于G 0/G1期，但不诱导细胞凋亡。然而，用DODC预处理的细胞显示出比未处理的细胞对砷更大的敏感性。两种药物联合处理引起的细胞凋亡百分比增加，与单独高剂量砷处理的效果相似。进一步的研究表明，DODC单独作用可诱导发夹状G-四链体的形成，并以剂量依赖的方式抑制端粒酶活性。与HT 1080细胞相比，293细胞对细胞生长抑制和凋亡更敏感，对端粒酶活性的敏感性较低。这些结果表明，DODC可以协同增强砷诱导的细胞凋亡，这表明砷引起的细胞衰老增加是由端粒状态改变而不是端粒酶丢失引起的。因此，砷剂联合端粒酶抑制剂的临床应用在肿瘤治疗中具有潜在的应用价值。
In this work, we investigated the synergic effects between low-dose arsenic trioxide and diethyloxadicarbocyanine (DODC), a telomerase inhibitor, on cell apoptosis. Results revealed that low-dose arsenic could block cell cycle arrest at the G2/M phase and induce apoptosis, whereas DODC could block cell cycle arrest at the G0/G1 phase but not induce apoptosis. However, cells pretreated with DODC showed greater sensitivity to arsenic than untreated cells. The percentage of apoptosis produced by combination treatment with the two agents increased and that was similar to the effect of high-dose arsenic treatment alone. Further studies showed that DODC alone could induce hairpin G-quadruplex formation and inhibit telomerase activity in a dose-dependent manner. Compared with HT1080 cells, 293 cells were more sensitive to cell growth inhibition and apoptosis and were less sensitivity to telomerase activity. These results indicate that DODC can synergistically enhance the apoptosis induced by arsenic, suggesting the increased cell senescence in response to arsenic is induced by an altered telomere state rather than by a loss of telomerase. Thus clinical application of combination treatment with arsenic and telomerase inhibitor may have potential in cancer therapy.