Metal Compounds Induce DNA Instability in Cancer Cells



July 21, 2021

Oncotarget’s cover paper this week (Volume 12, Issue 15) is entitled, "Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells," by researchers from Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; Chemistry and Modelling for the Biology of Cancer, CNRS UMR 9187-INSERM U1196 Institute Curie, Research Center, Campus University Paris-Saclay, Orsay, France; Laboratory of Chromosome Engineering, Department of Frontier Research and Development, Kazusa DNA Research Institute, Kisarazu, Chiba, Japan; Wellcome Centre for Cell Biology, School of Biological Sciences, King's Buildings, University of Edinburgh, Max Born Crescent, Edinburgh, Scotland. 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. Sign up for free Altmetric alerts about this article - DOI - Full text - Correspondence to - Vladimir Larionov - and Natalay Kouprina - Keywords - chromosome instability, CIN, platinum-derived G4-quadruplexes, telomere dysfunction, human artificial chromosome About Oncotarget Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit or connect with: SoundCloud - Facebook - Twitter - YouTube - LinkedIn - Pinterest - Reddit - Oncotarget is published by Impact Journals, LLC please visit or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

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