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Telomere Length and Telomerase Activity; A Yin and Yang of Cell Senescence
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Published on: May 22, 2013

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

Hee-Sheung Lee1, Mar Carmena2, Mikhail Liskovykh1

  • 1Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD.

Cancer Research
|September 1, 2018
PubMed

Insights

A new assay screens compounds targeting telomeres and telomerase, crucial for cancer treatment. This method identifies drugs that cause chromosome loss in cancer cells, potentially leading to new therapies.

Area of Science:

  • Cancer Research
  • Molecular Biology
  • Drug Discovery

Background:

  • Telomerase and telomere maintenance are vital targets for cancer therapy.
  • Existing methods for screening telomere-targeting compounds are limited.
  • Developing novel assays is crucial for identifying effective anti-cancer drugs.

Purpose of the Study:

  • To design and validate a novel assay for screening and ranking compounds targeting telomeres and telomerase.
  • To identify novel compounds that induce telomere dysfunction and chromosome mis-segregation in cancer cells.
  • To expedite the development of new therapeutic strategies for cancer treatment.

Main Methods:

  • Utilized two isogenic cell lines with circular and linear human artificial chromosomes (HACs) marked with EGFP.
  • Compounds preferentially inducing loss of the linear HAC (with telomeres) were identified via flow cytometry.
  • Assessed mitotic phenotypes, including chromatin bridges and ultrafine bridges (UFBs), and telomere-associated DNA damage.

Main Results:

  • Successfully applied the dual-HAC assay to screen and rank known and novel compounds, including G-quadruplex ligands.
  • Identified two G-quadruplex ligands, Cu-ttpy and Pt-ttpy, that induced significant linear HAC loss without affecting circular HAC stability.
  • Observed elevated chromatin bridges, UFBs, and telomere-associated DNA damage following treatment with Pt-ttpy or Cu-ttpy.

Conclusions:

  • The developed dual-HAC assay platform effectively identifies and ranks compounds that increase chromosome mis-segregation via telomere dysfunction.
  • Pt-ttpy and Cu-ttpy demonstrate potential as therapeutic agents by inducing telomere-related DNA damage and chromosome loss.
  • This platform holds promise for accelerating the discovery of new anti-cancer treatments targeting telomere maintenance mechanisms.

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