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.

我们选择并研究了九种形成G-四链体（G4）的适体，这些适体最初针对参与细胞增殖调节的不同蛋白质（STAT3，核仁素，TOP1，SP1，VEGF和SHP-2）设计，并被认为是潜在的抗癌剂。我们表明，在生理条件下，所有适体均形成具有不同拓扑结构的稳定G4。针对STAT3，核仁素和SP1设计的G4适体可抑制人乳腺癌MCF-7细胞中的STAT3转录活性，并且所有已研究的适体均能抑制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的抑制作用为最近描述的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。从头开始DNA合成，最多可达到79–87％。七种G4适体对人乳腺腺癌MCF-7细胞的抗增殖活性明显高于对永生化的乳腺上皮MCF-10A细胞的抗增殖活性。在大多数研究的G4适体中观察到的G4适体的多向性特性及其对癌细胞的高特异性，使我们能够将其作为多靶点癌症治疗的有希望的候选者。