N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health, Moscow, Russian Federation.
N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health, Moscow, Russian Federation; Department of Biology, Tufts University, Medford, MA, USA.
Biochimie. 2018 Feb;145:163-173. doi: 10.1016/j.biochi.2017.11.020. Epub 2017 Dec 5.
We selected and investigated nine G-quadruplex (G4)-forming aptamers originally designed against different proteins involved in the regulation of cellular proliferation (STAT3, nucleolin, TOP1, SP1, VEGF, and SHP-2) and considered to be potential anticancer agents. We showed that under physiological conditions all the aptamers form stable G4s of different topology. G4 aptamers designed against STAT3, nucleolin and SP1 inhibit STAT3 transcriptional activity in human breast adenocarcinoma MCF-7 cells, and all the studied aptamers inhibit TOP1-mediated relaxation of supercoiled plasmid DNA. STAT3 inhibition by G4 aptamer designed against SP1 protein provides a new explanation for the SP1 and STAT3 crosstalk described recently. We found some correlation between G4-mediated inhibition of the DNA replication and TOP1 activity. Four G4 aptamers from our dataset that appeared to be the strongest TOP1 inhibitors most efficiently decreased de novo DNA synthesis, by up to 79-87%. Seven G4 aptamers demonstrated significantly higher antiproliferative activity on human breast adenocarcinoma MCF-7 cells than on immortalized mammary epithelial MCF-10A cells. Pleiotropic properties of G4 aptamers and their high specificity against cancer cells observed for the majority of the studied G4 aptamers allowed us to present them as promising candidates for multi-targeted cancer therapy.
我们选择并研究了最初针对不同参与细胞增殖调节的蛋白质（STAT3、核仁素、TOP1、SP1、VEGF 和 SHP-2）设计的九个 G-四链体 (G4) 形成适体，并认为它们是潜在的抗癌药物。我们表明，在生理条件下，所有适体均形成不同拓扑结构的稳定 G4。针对 STAT3、核仁素和 SP1 设计的 G4 适体抑制人乳腺癌 MCF-7 细胞中 STAT3 的转录活性，所有研究的适体均抑制 TOP1 介导的超螺旋质粒 DNA 的松弛。针对 SP1 蛋白设计的 G4 适体对 STAT3 的抑制为最近描述的 SP1 和 STAT3 串扰提供了新的解释。我们发现 G4 介导的 DNA 复制抑制与 TOP1 活性之间存在一些相关性。我们数据集的四个 G4 适体似乎是最强的 TOP1 抑制剂，它们最有效地将从头合成的 DNA 减少了 79-87%。七种 G4 适体对人乳腺癌 MCF-7 细胞的增殖活性明显高于永生化乳腺上皮 MCF-10A 细胞。我们观察到大多数研究的 G4 适体对 G4 适体的多效性和对癌细胞的高特异性，认为它们是多靶点癌症治疗的有前途的候选药物。
