Synergistic potentiation of (-)-lomaiviticin A cytotoxicity by the ATR inhibitor VE-821

Bioorg Med Chem Lett. 2016 Jul 1;26(13):3122-3126. doi: 10.1016/j.bmcl.2016.04.090. Epub 2016 Apr 30.

Abstract

(-)-Lomaiviticin A (1) is a cytotoxic bacterial metabolite that induces double-strand breaks in DNA. Here we show that the cytotoxicity of (-)-lomaiviticin A (1) is synergistically potentiated in the presence of VE-821 (7), an inhibitor of ataxia telangiectasia and Rad3-related protein (ATR). While 0.5nM 1 or 10μM 7 alone are non-lethal to K562 cells, co-incubation of the two leads to high levels of cell kill (81% and 94% after 24 and 48h, respectively). Mechanistic data indicate that cells treated with 1 and 7 suffer extensive DNA double-strand breaks and apoptosis. These data suggest combinations of 1 and 7 may be a valuable chemotherapeutic strategy.

Keywords: Cancer; Chemotherapy; DNA; Lomaiviticin; Natural product; Synergism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis / drug effects
  • Cell Survival / drug effects
  • DNA Breaks, Double-Stranded / drug effects
  • Dose-Response Relationship, Drug
  • Fluorenes / chemical synthesis
  • Fluorenes / chemistry
  • Fluorenes / pharmacology*
  • Humans
  • K562 Cells
  • Molecular Structure
  • Pyrazines / chemistry
  • Pyrazines / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfones / chemistry
  • Sulfones / pharmacology*

Substances

  • 3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide
  • Fluorenes
  • Pyrazines
  • Sulfones
  • lomaiviticin A