Priority Research Papers:
Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells
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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
|Vladimir Larionov,||email:||[email protected]|
|Natalay Kouprina,||email:||[email protected]|
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
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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