YM155 inhibits topoisomerase function

Mei Hong, Mingqiang Ren, Maria J Silva, Ananya Paul, W. David Wilson, Carsten Schroeder, Paul Maurice Weinberger, John Edward Janik, Zhonglin Hao

Research output: Contribution to journalArticle

4 Citations (Scopus)

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

Fingerprint

DNA
Intercalating Agents
DNA Cleavage
Double-Stranded DNA Breaks
Circular Dichroism
S Phase
Mitosis
Viscosity
Spectrum Analysis
Cell Cycle
Clinical Trials
Enzymes
YM 155

Keywords

  • YM155
  • mitosis
  • repair
  • replication
  • topoisomerase

ASJC Scopus subject areas

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

Cite this

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

YM155 inhibits topoisomerase function. / Hong, Mei; Ren, Mingqiang; Silva, Maria J; Paul, Ananya; Wilson, W. David; Schroeder, Carsten; Weinberger, Paul Maurice; Janik, John Edward; Hao, Zhonglin.

In: Anti-Cancer Drugs, Vol. 28, No. 2, 13.10.2016, p. 142-152.

Research output: Contribution to journalArticle

Hong, M, Ren, M, Silva, MJ, Paul, A, Wilson, WD, Schroeder, C, Weinberger, PM, Janik, JE & Hao, Z 2016, 'YM155 inhibits topoisomerase function', Anti-Cancer Drugs, vol. 28, no. 2, pp. 142-152. https://doi.org/10.1097/CAD.0000000000000441
Hong M, Ren M, Silva MJ, Paul A, Wilson WD, Schroeder C et al. YM155 inhibits topoisomerase function. Anti-Cancer Drugs. 2016 Oct 13;28(2):142-152. https://doi.org/10.1097/CAD.0000000000000441
Hong, Mei ; Ren, Mingqiang ; Silva, Maria J ; Paul, Ananya ; Wilson, W. David ; Schroeder, Carsten ; Weinberger, Paul Maurice ; Janik, John Edward ; Hao, Zhonglin. / YM155 inhibits topoisomerase function. In: Anti-Cancer Drugs. 2016 ; Vol. 28, No. 2. pp. 142-152.
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