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Systematic Analysis of Compounds Specifically Targeting Telomeres and Telomerase for Clinical Implications in Cancer Therapy

Research output: Contribution to journalArticle

  • Hee-Sheung Lee
  • Mar Carmena
  • Mikhail Liskovykh
  • Emma Peat
  • Jung-Hyun Kim
  • Mitsuo Oshimura
  • Hiroshi Masumoto
  • Marie-Paule Teulade-Fichou
  • Yves Pommier
  • William C Earnshaw
  • Vladimir Larionov
  • Natalay Kouprina

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Original languageEnglish
JournalCancer Research
Early online date30 Aug 2018
DOIs
Publication statusE-pub ahead of print - 30 Aug 2018

Abstract

The targeting of telomerase and telomere maintenance mechanisms represents a promising therapeutic approach for various types of cancer. In this work, we designed a new protocol to screen for and rank the efficacy of compounds specifically targeting telomeres and telomerase. This approach used two isogenic cell lines containing a circular human artificial chromosome (HAC, lacking telomeres) and a linear HAC (containing telomeres) marked with the EGFP transgene: compounds that target telomerase or telomeres should preferentially induce loss of the linear HAC but not the circular HAC. Our assay allowed quantification of chromosome loss by routine flow cytometry. We applied this dual-HAC assay to rank a set of known and newly developed compounds, including G-quadruplex (G4) ligands. Among the latter group, two compounds -Cu-ttpy and Pt-ttpy- induced a high rate of linear HAC loss with no significant effect on the mitotic stability of a circular HAC. Analysis of the mitotic phenotypes induced by these drugs revealed an elevated rate of chromatin bridges in late mitosis and cytokinesis as well as UFB (Ultrafine Bridges). Chromosome loss after Pt-ttpy or Cu-ttpy treatment correlated with the induction of telomere-associated DNA damage. Overall, this platform enables identification and ranking of compounds that greatly increase chromosome mis-segregation rates as a result of telomere dysfunction and may expedite the development of new therapeutic strategies for cancer treatment.

    Research areas

  • chromosome instability, CIN, human artificial chromosome, HAC, telomerase inhibitors

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