YM155 induces oxidative stress-mediated DNA damage and cell cycle arrest, and causes programmed cell death in anaplastic thyroid cancer cells

Qinqin Xu, Ryan P. Mackay, Adam Y. Xiao, John A. Copland, Paul M. Weinberger

Research output: Contribution to journalArticlepeer-review

Abstract

Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies with a median survival time of about 4 months. Currently, there is no effective treatment, and the development of new therapies is an important and urgent issue for ATC patients. YM155 is a small molecule that was identified as the top candidate in a high-throughput screen of small molecule inhibitors per-formed against a panel of ATC cell lines by the National Cancer Institute. However, there were no follow-up studies investigating YM155 in ATC. Here, we determined the effects of YM155 on ATC and human primary benign thyroid cell (PBTC) survival with alamarBlue assay. Our data show that YM155 inhibited proliferation of ATC cell lines while sparing normal thyroid cells, suggesting a high therapeutic window. YM155-induced DNA damage was detected by measuring phosphoryla-tion of γ-H2AX as a marker for DNA double-strand breaks. The formamidopyrimidine-DNA gly-cosylase (FPG)-modified alkaline comet assay in conjunction with reactive oxygen species (ROS) assay and glutathione (GSH)/glutathione (GSSG) assay suggests that YM155-mediated oxidative stress contributes to DNA damage. In addition, we provide evidence that YM155 causes cell cycle arrest in S phase and in the G2/M transition and causes apoptosis, as seen with flow cytometry. In this study, we show for the first time the multiple effects of YM155 in ATC cells, furthering a potential therapeutic approach for ATC.

Original languageEnglish (US)
Article number1961
Pages (from-to)1-14
Number of pages14
JournalInternational journal of molecular sciences
Volume22
Issue number4
DOIs
StatePublished - Feb 2 2021

Keywords

  • Anaplastic thyroid cancer
  • Apoptosis
  • Cell cycle arrest
  • DNA damage
  • YM155

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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