Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells
| Autor: | Natalay Kouprina, Marie-Paule Teulade-Fichou, Yves Pommier, N. S. Petrov, Vladimir Larionov, Mikhail Liskovykh, William C. Earnshaw, Hee-Sheung Lee, Hiroshi Masumoto |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
human artificial chromosome
Telomerase DNA damage Chemistry HAC Platinum derived G4 quadruplexes platinum-derived G4-quadruplexes Chromatin Telomere telomere dysfunction Oncology Chromosome instability Cancer cell Cancer research CIN chromosome instability Mitosis Cytokinesis Priority Research Paper |
| Zdroj: | Petrov, N S, Lee, H-S, Liskovykh, M, Teulade-Fichou, M-P, Masumoto, H, Earnshaw, W C, Pommier, Y, Larionov, V & Kouprina, N 2021, ' Terpyridine platinum compounds induce telomere dysfunction and chromosome instability in cancer cells ', Oncotarget, vol. 12, pp. 1444-1456 . https://doi.org/10.18632/oncotarget.28020 Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.28020 |
| Popis: | Background 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. Method: 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. Conclusions These terpyridine platinum-derived G4 ligands are promising compounds for cancer treatment. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|