Oncotarget

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

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

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Oncotarget. 2021; 12:1444-1456. https://doi.org/10.18632/oncotarget.28020

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Abstract

Nikolai Petrov1, Hee-Sheung Lee1, Mikhail Liskovykh1, Marie-Paule Teulade-Fichou2, Hiroshi Masumoto3, William C. Earnshaw4, Yves Pommier1, Vladimir Larionov1 and Natalay Kouprina1

1 Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

2 Chemistry and Modelling for the Biology of Cancer, CNRS UMR 9187-INSERM U1196 Institute Curie, Research Center, Campus University Paris-Saclay, Orsay, France

3 Laboratory of Chromosome Engineering, Department of Frontier Research and Development, Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan

4 Wellcome Centre for Cell Biology, School of Biological Sciences, King's Buildings, University of Edinburgh, Max Born Crescent, Edinburgh EH9 3BF, Scotland

Correspondence to:

Vladimir Larionov,email: larionov@mail.nih.gov
Natalay Kouprina,email: kouprinn@mail.nih.gov

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

Received: April 13, 2021     Accepted: June 22, 2021     Published: July 20, 2021

Copyright: © 2021 Petrov et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.


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