Most cancers remedy with terpyridine platinum compounds induces telomere dysfunction, chromosome instability

Oncotarget revealed “Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in most cancers cells” which reported that this assay relies on the usage of two isogenic HT1080 cell strains, one carrying a linear HAC and the opposite carrying a round HAC.

Disruption of telomeres in response to drug remedy ends in particular destabilization of the linear HAC.

On this examine, they used the dual-HAC assay for the evaluation of the platinum-derived G4 ligand Pt-tpy and 5 of its derivatives: Pt-cpym, Pt-vpym, Pt-ttpy, Pt -tpy, and Pt-BisQ. Their evaluation revealed 4 compounds, Pt-tpy, Pt-ttpy, Pt-vpym and Pt-cpym, that induce a particular lack of a linear however not a round HAC.

Elevated CIN after remedy by these compounds correlates with the induction of double-stranded breaks predominantly localized at telomeres and reflecting telomere-associated DNA harm.

These terpyridine platinum-derived G4 ligands are promising compounds for most cancers remedy.

Dr. Vladimir Larionov and Dr. Natalay Kouprina each from The Nationwide Institutes of Well being stated, “Regular human somatic cells comprise 46 chromosomes.

Telomerase/telomere-targeting remedy is taken into account to be a doubtlessly promising strategy for most cancers remedy as a result of even transient telomere dysfunction can induce chromosomal instability in human cells.

The enzyme telomerase elongates telomeres and maintains a telomere size equilibrium that stops telomeres from changing into critically brief.

Particularly, formation of G4s at telomeres may impede telomerase recognition and inhibit telomere elongation resulting in telomere shortening.

Thus, telomeres are promising targets for discovery of ligands that stabilize G4s at telomeres, thereby perturbing telomere upkeep and resulting in genomic instability.

The authors discovered that remedy of most cancers cells with both Pt-cpym, Pt-vpym, Pt-ttpy or Pt-tpy induces telomere dysfunction resulting in excessive ranges of chromosome instability.

The Larionov/Kouprina Analysis Group concluded of their Oncotarget Analysis Output, “utilizing our dual-HAC assay we recognized three terpyridine platinum compounds, Pt-tpy, Pt-vpym and Pt-cpym, that induce a excessive stage of chromosome instability (CIN) as beforehand reported for the associated compound Pt-ttpy. CIN noticed after remedy of cells with these compounds correlates with the formation of double-stranded DNA breaks predominantly localized proximal to telomeres. The telomere-associated DNA harm induced by these medicine results in chromatin bridge formation in late mitosis and cytokinesis. This household of G4 ligands that induce telomere dysfunction and enormously enhance chromosome mis-segregation charges are promising drug candidates for remedy of most cancers alone or together with ionizing radiation.


Journal reference:

Petrov, N., et al. (2021) Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in most cancers cells. Oncotarget.

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