Oncotarget: Telomere dysfunction and chromosome instability in cancer cells

Oncotarget published "Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells" which reported that this assay is based on the use of two isogenic HT1080 cell lines, one carrying a linear HAC and the other carrying a circular HAC.

Disruption of telomeres in response to drug treatment results in specific destabilization of the linear HAC.

In this study, they used the dual-HAC assay for the analysis of the platinum-derived G4 ligand Pt-tpy and five of its derivatives: Pt-cpym, Pt-vpym, Pt-ttpy, Pt -tpy, and Pt-BisQ. Their analysis revealed four compounds, Pt-tpy, Pt-ttpy, Pt-vpym and Pt-cpym, that induce a specific loss of a linear but not a circular HAC.

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

These terpyridine platinum-derived G4 ligands are promising compounds for cancer treatment.

These terpyridine platinum-derived G4 ligands are promising compounds for cancer treatment.

Dr. Vladimir Larionov and Dr. Natalay Kouprina both from The National Institutes of Health said, "Normal human somatic cells contain 46 chromosomes."

Telomerase/telomere-targeting therapy is considered to be a potentially promising approach for cancer treatment because even transient telomere dysfunction can induce chromosomal instability in human cells.

The enzyme telomerase elongates telomeres and maintains a telomere length equilibrium that prevents telomeres from becoming critically short.

In particular, formation of G4s at telomeres could impede telomerase recognition and inhibit telomere elongation leading to telomere shortening.

Figure 6: Specific telomere aberrations in HT1080 cells induced by treatment of Pt-tpy and its derivatives, Pt-cpym, Pt-vpym and Pt-ttpy. (A–C) Histograms show the percentages of chromosomes with the indicated telomere damage per cell detected in metaphase spreads of treated versus untreated cells (DMSO) hybridized with a telomeric PNA probe (in red) and then counterstained with DAPI (in blue). ^*Indicates a t-test P-value < 0.05; ^**P < 0.01. (D and E) Representative images of the different telomere aberrations after Pt-ttpy treatment. TD-telomere doublets; STL-single telomere loss; SCF-sister chromatid fusion; DEL-terminal deletion.

Thus, telomeres are promising targets for discovery of ligands that stabilize G4s at telomeres, thereby perturbing telomere maintenance and leading to genomic instability.

The authors found that treatment of cancer cells with either Pt-cpym, Pt-vpym, Pt-ttpy or Pt-tpy induces telomere dysfunction leading to high levels of chromosome instability.

The Larionov/Kouprina Research Team concluded in their Oncotarget Research Output, "using our dual-HAC assay we identified three terpyridine platinum compounds, Pt-tpy, Pt-vpym and Pt-cpym, that induce a high level of chromosome instability (CIN) as previously reported for the related compound Pt-ttpy. CIN observed after treatment of cells with these compounds correlates with the formation of double-stranded DNA breaks predominantly localized proximal to telomeres. The telomere-associated DNA damage induced by these drugs leads to chromatin bridge formation in late mitosis and cytokinesis. This family of G4 ligands that induce telomere dysfunction and greatly increase chromosome mis-segregation rates are promising drug candidates for treatment of cancer alone or in combination with ionizing radiation."

DOI - https://doi.org/10.18632/oncotarget.28020

Full text - https://www.oncotarget.com/article/28020/text/

Correspondence to - Vladimir Larionov - larionov@mail.nih.gov and Natalay Kouprina - kouprinn@mail.nih.gov

Keywords - chromosome instability, CIN, platinum-derived G4-quadruplexes, telomere dysfunction, human artificial chromosome

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