Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands
Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands
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DOI：
10.1073/pnas.052698099
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发表时间：
2002-03-05
影响因子：
11.1
通讯作者：
Mergny, JL
中科院分区：
文献类型：
--
作者：
Riou, JF;Guittat, L;Mergny, JL
人类染色体的端粒含有一个富含G的3‘-突起，在体外采用了分子内G-四链结构，从而阻断了端粒酶的催化反应。稳定G-四链体的药物有可能通过阻断端粒酶催化的延长步骤来干扰端粒复制，因此可以作为抗肿瘤药物。我们已经通过荧光共振能量转移确定了一系列新的基于喹啉的G-四链配体，这些配体也表现出有效和特异的抗端粒酶活性，IC50在纳摩尔浓度范围内。肿瘤细胞在亚凋亡剂量下的长期治疗会导致延迟的生长停滞，这取决于初始端粒长度。这种生长停滞与端粒侵蚀和衰老细胞表型(大尺寸和表达β-半乳糖苷酶活性)的出现有关。我们的数据表明，G-四链相互作用剂能够损害肿瘤细胞的端粒酶功能，从而为开发新的抗癌药物提供了基础。
Telomeres of human chromosomes contain a G-rich 3'-overhang that adopts an intramolecular G-quadruplex structure in vitro which blocks the catalytic reaction of telomerase. Agents that stabilize G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalyzed by telomerase and can therefore act as antitumor agents. We have identified by Fluorescence Resonance Energy Transfer a new series of quinoline-based G-quadruplex ligands that also exhibit potent and specific anti-telomerase activity with IC50 in the nanomolar concentration range. Long term treatment of tumor cells at subapoptotic dosage induces a delayed growth arrest that depends on the initial telomere length. This growth arrest is associated with telomere erosion and the appearance of the senescent cell phenotype (large size and expression of beta-galactosidase activity). Our data show that a G-quadruplex interacting agent is able to impair telomerase function in a tumor cell thus providing a basis for the development of new anticancer agents.