Asymmetric triplex metallohelices stabilise DNA G-quadruplexes in promoter oncogene sequences and efficiently reduce their expression in cancer cells

Some metallo-supramolecular helical assemblies with size, shape, charge and amphipathic architectures similar to short cationic α-helical peptides have been shown to target and stabilise DNA G-quadruplexes (G4s) in vitro and downregulate the expression of G4-regulated genes in human cells. To expand...

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Bibliographic Details
Published in:Journal of enzyme inhibition and medicinal chemistry 2023-12, Vol.38 (1), p.2198678-2198678
Main Authors: Malina, Jaroslav, Kostrhunova, Hana, Song, Hualong, Scott, Peter, Brabec, Viktor
Format: Article
Language:English
Subjects:
Biophysics
c-Kit protein
c-Myc protein
Cancer
Deoxyribonucleic acid
DNA
DNA - chemistry
DNA polymerase
DNA synthesis
DNA-directed DNA polymerase
Down-regulation
expression of oncogenes
G-Quadruplexes
Humans
Metallohelices
mRNA
Myc protein
Neoplasms
Nucleotide sequence
Oncogenes
Promoter Regions, Genetic
Research Paper
telomeres
Western blotting
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Summary:Some metallo-supramolecular helical assemblies with size, shape, charge and amphipathic architectures similar to short cationic α-helical peptides have been shown to target and stabilise DNA G-quadruplexes (G4s) in vitro and downregulate the expression of G4-regulated genes in human cells. To expand the library of metallohelical structures that can act as efficient DNA G4 binders and downregulate genes containing G4-forming sequences in their promoter regions, we investigated the interaction of the two enantiomeric pairs of asymmetric Fe(II) triplex metallohelices with a series of five different DNA G4s formed by the human telomeric sequence (hTelo) and in the promoter regions of c-MYC, c-KIT, and k-RAS oncogenes. The metallohelices display preferential binding to G4s over duplex DNA in all investigated G4-forming sequences and induced arrest of DNA polymerase on template strands containing G4-forming sequences. Moreover, the investigated metallohelices suppressed the expression of c-MYC and k-RAS genes at mRNA and protein levels in HCT116 human cancer cells, as revealed by RT-qPCR analysis and western blotting.
ISSN:1475-6366
1475-6374
DOI:10.1080/14756366.2023.2198678