Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells.

Nikolai Petrov,Yves Pommier,Mikhail Liskovykh,Natalay Kouprina,Marie-Paule Teulade-Fichou,Vladimir Larionov,William C. Earnshaw,Hiroshi Masumoto,Hee-Sheung Lee

doi:10.18632/oncotarget.28020

Abstract

Telomerase/telomere-targeting therapy is a potentially promising approach for cancer treatment because even transient telomere dysfunction can induce chromosomal instability (CIN) and may be a barrier to tumor growth. We recently developed a dual-HAC (Human Artificial Chromosome) assay that enables identification and ranking of compounds that induce CIN as a result of telomere dysfunction. This assay is based on the use of two isogenic HT1080 cell lines, one carrying a linear HAC (containing telomeres) and the other carrying a circular HAC (lacking telomeres). Disruption of telomeres in response to drug treatment results in specific destabilization of the linear HAC. Results: In this study, we 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(PA)-tpy, and Pt-BisQ. Our 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 (DSBs) predominantly localized at telomeres and reflecting telomere-associated DNA damage. Analysis of the mitotic phenotypes induced by these drugs revealed an elevated rate of chromatin bridges (CBs) in late mitosis and cytokinesis. These terpyridine platinum-derived G4 ligands are promising compounds for cancer treatment.

Highlights

Normal human somatic cells contain 46 chromosomes
We found that treatment of cancer cells with either Pt-cpym, Pt-vpym, Ptttpy or Pt-tpy induces telomere dysfunction leading to high levels of chromosome instability
We examined whether the γH2AX foci colocalize with or are adjacent to the telomeric protein telomeric repeat binding factor 2 (TRF2) in order to assess whether the deoxyribonucleic acid (DNA) damage is associated with telomeric sequences

Summary

Introduction

Normal human somatic cells contain 46 chromosomes. A distinguishing feature of many cancer cells is whole-chromosomal instability (CIN) manifested as unequal chromosome distribution during cell division. The number of chromosomes deviates from the modal number of 46. Such chromosome missegregation can lead to large-scale changes in gene copy number and gene expression levels. That study revealed that there is a threshold level beyond which CIN becomes a barrier to tumor growth. The authors reported that treatment with drugs that target the mitotic checkpoint or interfere with chromosome alignment enhances the amount and severity of chromosome segregation errors and leads to selective www.oncotarget.com killing of tumor cells. Subsequent studies confirmed that interference with chromosome segregation can push genetically unstable cancer cells towards death, whereas more stable non-transformed cells are better able to tolerate such insults [2,3,4]

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