CFS-1686 Causes Cell Cycle Arrest at intra-S Phase by Interference of Interaction of Topoisomerase 1 With DNA

PLoS One. 2014 Dec 2;9(12):e113832. doi: 10.1371/journal.pone.0113832. eCollection 2014.

Abstract

CFS-1686 (chemical name (E)-N-(2-(diethylamino)ethyl)-4-(2-(2-(5-nitrofuran-2-yl)vinyl)quinolin-4-ylamino)benzamide) inhibits cell proliferation and triggers late apoptosis in prostate cancer cell lines. Comparing the effect of CFS-1686 on cell cycle progression with the topoisomerase 1 inhibitor camptothecin revealed that CFS-1686 and camptothecin reduced DNA synthesis in S-phase, resulting in cell cycle arrest at the intra-S phase and G1-S boundary, respectively. The DNA damage in CFS-1686 and camptothecin treated cells was evaluated by the level of ATM phosphorylation, γH2AX, and γH2AX foci, showing that camptothecin was more effective than CFS-1686. However, despite its lower DNA damage capacity, CFS-1686 demonstrated 4-fold higher inhibition of topoisomerase 1 than camptothecin in a DNA relaxation assay. Unlike camptothecin, CFS-1686 demonstrated no activity on topoisomerase 1 in a DNA cleavage assay, but nevertheless it reduced the camptothecin-induced DNA cleavage of topoisomerase 1 in a dose-dependent manner. Our results indicate that CFS-1686 might bind to topoisomerase 1 to inhibit this enzyme from interacting with DNA relaxation activity, unlike campothecin's induction of a topoisomerase 1-DNA cleavage complex. Finally, we used a computer docking strategy to localize the potential binding site of CFS-1686 to topoisomerase 1, further indicating that CFS-1686 might inhibit the binding of Top1 to DNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / chemistry
  • Aminoquinolines / pharmacology*
  • Apoptosis / drug effects
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Binding Sites
  • Camptothecin / pharmacology
  • Cell Cycle Checkpoints / drug effects*
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Topoisomerases, Type I / metabolism*
  • DNA, Neoplasm / metabolism*
  • Humans
  • Male
  • Models, Biological
  • Molecular Docking Simulation
  • S Phase / drug effects*

Substances

  • Aminoquinolines
  • Benzamides
  • CFS-1686
  • DNA, Neoplasm
  • DNA Topoisomerases, Type I
  • Camptothecin

Grant support

This work was supported by Grant NSC99-2320-B-037-013-MY3 (to CW) from Ministry of Science and Technology of Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.