YM155 inhibits topoisomerase function

Mei Hong, Ming Qiang Ren, Jeane Silva, Ananya Paul, W. David Wilson, Carsten Schroeder, Paul Weinberger, John Janik, Zhonglin Hao

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

YM155 (sepantronium bromide) has been evaluated in clinical trials as a survivin suppressant, but despite positive signals from early work, later studies were negative. Clarification of the mechanism of action of YM155 is important for its further development. YM155 affects cells in a cell cycle-specific manner. When cells are in G1, YM155 prevented their progression through the S phase, leaving the cells at G1/S when exposed to YM155. Passage through mitosis from G2 is also defective following YM155 exposure. In this study, YM155 did not behave like a typical DNA intercalator in viscosity, circular dichroism, and absorption spectroscopy studies. In addition, molecular modeling experiments ruled out YM155 DNA interaction to produce DNA intercalation. We show that YM155 inhibited topoisomerase 2α decatenation and topoisomerase 1-mediated cleavage of DNA, suggesting that YM155 inhibits the enzyme function. Consistent with these findings, DNA double-strand break repair was also inhibited by YM155.

Original languageEnglish (US)
Pages (from-to)142-152
Number of pages11
JournalAnti-Cancer Drugs
Volume28
Issue number2
DOIs
StatePublished - Oct 13 2016

Keywords

  • YM155
  • mitosis
  • repair
  • replication
  • topoisomerase

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

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  • Cite this

    Hong, M., Ren, M. Q., Silva, J., Paul, A., Wilson, W. D., Schroeder, C., Weinberger, P., Janik, J., & Hao, Z. (2016). YM155 inhibits topoisomerase function. Anti-Cancer Drugs, 28(2), 142-152. https://doi.org/10.1097/CAD.0000000000000441