Ellipticine Binds to a Human Telomere Sequence: An Additional Mode of Action as a Putative Anticancer Agent?
Ellipticine Binds to a Human Telomere Sequence: An Additional Mode of Action as a Putative Anticancer Agent?
复制标题
DOI：
10.1021/bi400080t
复制
发表时间：
2013-06-18
期刊：
影响因子：
2.9
通讯作者：
Dasguptat, Dipak
中科院分区：
文献类型：
--
作者：
Ghosh, Saptaparni;Kar, Anirban;Dasguptat, Dipak
聚鸟嘌呤序列在单价阳离子存在下折叠成G-四链体结构。端粒DNA区域由G-四链体结构组成。有报道称，潜在的G-四链体形成基序也存在于一些原癌基因的启动子区域，如c-myc，c-kit，KRAS等。具有稳定端粒DNA四链体潜力的小分子已成为潜在的抗癌药物。我们已经研究了相互作用的椭圆树碱，一个假定的抗癌剂从植物来源，与人类端粒DNA序列（H24）。光谱和量热研究表明，与H24的椭圆树碱协会是一个熵驱动的现象与2：3（H24：椭圆树碱）的化学计量比。虽然椭圆藤碱结合不引起任何重大的结构扰动H24，协会导致形成的复合物具有增强的热稳定性。用端粒酶重复扩增方案进行的测定显示椭圆树碱抑制MDAMB-231乳腺癌细胞系提取物中的端粒酶活性。这是首次报道椭圆藤碱的四链体结合能力。利用这些结果，我们提出，沿着DNA嵌入和/或拓扑异构酶II抑制，与端粒DNA区域的相互作用和由此产生的端粒酶活性抑制可能是其抗癌性质的另一种作用模式。
Polyguanine sequences fold into G-quadruplex structures in the presence of monovalent cations. It is accepted that the telomeric DNA region consists of G-quadruplex structure. There are reports that potential G-quadruplex forming motifs are also present in the promoter region of some proto-oncogenes such as c-myc, c-kit, KRAS, etc. Small molecules with the potential to stabilize the telomeric DNA quadruplex have emerged as potential anticancer agents. We have studied the interaction of ellipticine, a putative anticancer agent from a plant source, with a human telomeric DNA sequence (H24). Spectroscopic and calorimetric studies indicate that the association of ellipticine with H24 is an entropically driven phenomenon with a 2:3 (H24:ellipticine) stoichiometry. Though ellipticine binding does not induce any major structural perturbation in H24, the association leads to formation of a complex with enhanced thermal stability. An assay with the telomerase repeat amplification protocol shows that ellipticine inhibits telomerase activity in MDAMB-231 breast cancer cell line extracts. This is the first report of the quadruplex binding ability of ellipticine. Using the results, we propose that along with DNA intercalation and/or topoisomerase II inhibition, interaction with the telomeric DNA region and the resultant inhibition of telomerase activity might be an additional mode of action for its anticancer property.