Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Petrov, Nikolai, Lee, Hee-Sheung, Liskovykh, Mikhail, Teulade-Fichou, Marie-Paule, Masumoto, Hiroshi, Earnshaw, William C., Pommier, Yves, Larionov, Vladimir, Kouprina, Natalay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2021
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
_version_ 1783728811258413056
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
work_keys_str_mv AT petrovnikolai terpyridineplatinumcompoundsinducetelomeredysfunctionandchromosomeinstabilityincancercells
AT leeheesheung terpyridineplatinumcompoundsinducetelomeredysfunctionandchromosomeinstabilityincancercells
AT liskovykhmikhail terpyridineplatinumcompoundsinducetelomeredysfunctionandchromosomeinstabilityincancercells
AT teuladefichoumariepaule terpyridineplatinumcompoundsinducetelomeredysfunctionandchromosomeinstabilityincancercells
AT masumotohiroshi terpyridineplatinumcompoundsinducetelomeredysfunctionandchromosomeinstabilityincancercells
AT earnshawwilliamc terpyridineplatinumcompoundsinducetelomeredysfunctionandchromosomeinstabilityincancercells
AT pommieryves terpyridineplatinumcompoundsinducetelomeredysfunctionandchromosomeinstabilityincancercells
AT larionovvladimir terpyridineplatinumcompoundsinducetelomeredysfunctionandchromosomeinstabilityincancercells
AT kouprinanatalay terpyridineplatinumcompoundsinducetelomeredysfunctionandchromosomeinstabilityincancercells