Multi-targeted effects of G4-aptamers and their antiproliferative activity against cancer cells

Ogloblina, Anna; Khristich, Alexandra N.; Karpechenko, Natalia Y.; Semina, Svetlana E.; Belitsky, Gennady A.; Dolinnaya, Nina G.; Yakubovskaya, Marianna G.

doi:10.1016/j.biochi.2017.11.020

Cited by 23 publications

(31 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Multi-targeted effect of G-quadruplex-based aptamers described in [76] enable their interference with integral cellular processes, such as modulation of telomerase activity [56], proliferation of breast adenocarcinoma cells [76], suppression of inflammasome activity in macrophages [77]. In this study, we demonstrated that synthetic ODNs based on G-quadruplex-forming telomere repeats (d(TTAGGG) 4 ) and their modified analogues significantly activate the leukotriene synthesis and other key cellular responses of human neutrophils.…”

Section: Discussionmentioning

confidence: 85%

The Potential of Telomeric G-Quadruplexes Containing Modified Oligoguanosine Overhangs in Activation of Bacterial Phagocytosis and Leukotriene Synthesis in Human Neutrophils

et al. 2020

Self Cite

View full text Add to dashboard Cite

Human neutrophils are the first line of defense against bacterial and viral infections. They eliminate pathogens through phagocytosis, which activate the 5-lipoxygenase (5-LOX) pathway resulting in synthesis of leukotrienes. Using HPLC analysis, flow cytometry, and other biochemical methods, we studied the effect of synthetic oligodeoxyribonucleotides (ODNs) able to fold into G-quadruplex structures on the main functions of neutrophils. Designed ODNs contained four human telomere TTAGGG repeats (G4) including those with phosphorothioate oligoguanosines attached to the end(s) of G-quadruplex core. Just modified analogues of G4 was shown to more actively than parent ODN penetrate into cells, improve phagocytosis of Salmonella typhimurium bacteria, affect 5-LOX activation, the cytosol calcium ion level, and the oxidative status of neutrophils. As evident from CD and UV spectroscopy data, the presence of oligoguanosines flanking G4 sequence leads to dramatic changes in G-quadruplex topology. While G4 folds into a single antiparallel structure, two main folded forms have been identified in solutions of modified ODNs: antiparallel and dominant, more stable parallel. Thus, both the secondary structure of ODNs and their ability to penetrate into the cytoplasm of cells are important for the activation of neutrophil cellular effects. Our results offer new clues for understanding the role of G-quadruplex ligands in regulation of integral cellular processes and for creating the antimicrobial agents of a new generation.

show abstract

Section: Discussionmentioning

confidence: 85%

The Potential of Telomeric G-Quadruplexes Containing Modified Oligoguanosine Overhangs in Activation of Bacterial Phagocytosis and Leukotriene Synthesis in Human Neutrophils

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Aptamers targeting proteins or other biologically relevant molecules have been selected by screening libraries of DNA or RNA oligos and further studied for the potential therapeutic application. Since it was first discovered that Top1 binds and is inhibited by G4-forming oligos [37,38], other similar results have been reported [39,48,49]. First, using purified Calf Thymus Top1, Shuai et al characterized fourteen different guanine-rich oligos capable of forming either G-quadruplex or quadruplex-duplex hybrid and showed that all of the oligos act as competitive inhibitors of Top1 catalysis [39].…”

Section: G4 Oligos As Top1 Inhibiting Aptamersmentioning

confidence: 83%

“…They were even more effective in inhibiting Top1 when compared to the aptamer first identified as a Top1-specific inhibitor by Shuai et al [39]. The inhibition of Top1 by the G4 oligos was correlated with the inhibition of DNA replication, and this antiproliferative effect was specific to cancer cells [49]. Although the physical interaction between the G4-capable aptamers and Top1 was not determined in these studies, the specific nature of the inhibition strongly suggests that the competitive binding of the aptamers to Top1 underlies the inhibition of the catalytic activity.…”

Section: And D(cactgg-cc-(gggt) 4 -Ta-ccagtg)mentioning

confidence: 96%

“…But the longer oligo proved to be a more effective Top1 inhibitor with IC 50 of 0.08 µM. In another study, six different guanine-rich aptamers were tested for their inhibitory effect on human Top1 [49]. These aptamers were previously designed to target other oncogenic proteins, namely STAT3, SP1, VEGF, NCL, and SHP-2, and commonly formed either parallel or anti-parallel G4 DNAs that are significantly stabilized by the presence of potassium cation as expected.…”

Section: And D(cactgg-cc-(gggt) 4 -Ta-ccagtg)mentioning

confidence: 99%

See 1 more Smart Citation

The Functional Consequences of Eukaryotic Topoisomerase 1 Interaction with G-Quadruplex DNA

Berroyer

Kim

2020

Genes

View full text Add to dashboard Cite

Topoisomerase I in eukaryotic cells is an important regulator of DNA topology. Its catalytic function is to remove positive or negative superhelical tension by binding to duplex DNA, creating a reversible single-strand break, and finally religating the broken strand. Proper maintenance of DNA topological homeostasis, in turn, is critically important in the regulation of replication, transcription, DNA repair, and other processes of DNA metabolism. One of the cellular processes regulated by the DNA topology and thus by Topoisomerase I is the formation of non-canonical DNA structures. Non-canonical or non-B DNA structures, including the four-stranded G-quadruplex or G4 DNA, are potentially pathological in that they interfere with replication or transcription, forming hotspots of genome instability. In this review, we first describe the role of Topoisomerase I in reducing the formation of non-canonical nucleic acid structures in the genome. We further discuss the interesting recent discovery that Top1 and Top1 mutants bind to G4 DNA structures in vivo and in vitro and speculate on the possible consequences of these interactions.

show abstract

“…G4-aptamers have been extensively documented as therapeutic agents able to activate potent antiproliferative effects in a variety of cancer cell lines [7]. Among G4-aptamers, the anticancer AS1411 is the only one for which Phase II has been completed [41].…”

Section: Discussionmentioning

confidence: 99%

uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells

et al. 2020

View full text Add to dashboard Cite

The antiproliferative G-quadruplex aptamers are a promising and challenging subject in the framework of the anticancer therapeutic oligonucleotides research field. Although several antiproliferative G-quadruplex aptamers have been identified and proven to be effective on different cancer cell lines, their mechanism of action is still unexplored. We have recently described the antiproliferative activity of a heterochiral thrombin binding aptamer (TBA) derivative, namely, LQ1. Here, we investigate the molecular mechanisms of LQ1 activity and the structural and antiproliferative properties of two further TBA derivatives, differing from LQ1 only by the small loop base-compositions. We demonstrate that in p53 deleted colon cancer cells, LQ1 causes nucleolar stress, impairs ribosomal RNA processing, leading to the accumulation of pre-ribosomal RNAs, arrests cells in the G2/M phase and induces early apoptosis. Importantly, the depletion of uL3 abrogates all these effects, indicating that uL3 is a crucial player in the mechanism of action of LQ1. Taken together, our findings identify p53-independent and uL3-dependent nucleolar stress as a novel stress response pathway activated by a specific G-quadruplex TBA derivative. To the best of our knowledge, this investigation reveals, for the first time, the involvement of the nucleolar stress pathway in the mechanism of action of antiproliferative G-quadruplex aptamers.

show abstract

Multi-targeted effects of G4-aptamers and their antiproliferative activity against cancer cells

Cited by 23 publications

References 48 publications

The Potential of Telomeric G-Quadruplexes Containing Modified Oligoguanosine Overhangs in Activation of Bacterial Phagocytosis and Leukotriene Synthesis in Human Neutrophils

The Potential of Telomeric G-Quadruplexes Containing Modified Oligoguanosine Overhangs in Activation of Bacterial Phagocytosis and Leukotriene Synthesis in Human Neutrophils

The Functional Consequences of Eukaryotic Topoisomerase 1 Interaction with G-Quadruplex DNA

uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells

Contact Info

Product

Resources

About