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Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells
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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310675/ https://www.ncbi.nlm.nih.gov/pubmed/34316326 http://dx.doi.org/10.18632/oncotarget.28020 |
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author | Petrov, Nikolai Lee, Hee-Sheung Liskovykh, Mikhail Teulade-Fichou, Marie-Paule Masumoto, Hiroshi Earnshaw, William C. Pommier, Yves Larionov, Vladimir Kouprina, Natalay |
author_facet | Petrov, Nikolai Lee, Hee-Sheung Liskovykh, Mikhail Teulade-Fichou, Marie-Paule Masumoto, Hiroshi Earnshaw, William C. Pommier, Yves Larionov, Vladimir Kouprina, Natalay |
author_sort | Petrov, Nikolai |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8310675 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-83106752021-07-26 Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells Petrov, Nikolai Lee, Hee-Sheung Liskovykh, Mikhail Teulade-Fichou, Marie-Paule Masumoto, Hiroshi Earnshaw, William C. Pommier, Yves Larionov, Vladimir Kouprina, Natalay Oncotarget Priority Research Paper 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. Impact Journals LLC 2021-07-20 /pmc/articles/PMC8310675/ /pubmed/34316326 http://dx.doi.org/10.18632/oncotarget.28020 Text en Copyright: © 2021 Petrov et al. https://creativecommons.org/licenses/by/3.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Priority Research Paper Petrov, Nikolai Lee, Hee-Sheung Liskovykh, Mikhail Teulade-Fichou, Marie-Paule Masumoto, Hiroshi Earnshaw, William C. Pommier, Yves Larionov, Vladimir Kouprina, Natalay Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells |
title | Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells |
title_full | Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells |
title_fullStr | Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells |
title_full_unstemmed | Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells |
title_short | Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells |
title_sort | terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells |
topic | Priority Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310675/ https://www.ncbi.nlm.nih.gov/pubmed/34316326 http://dx.doi.org/10.18632/oncotarget.28020 |
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