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

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.

• Authors: Laureen C Colis, Seth B Herzon
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 26 Issue 13 Pg. 3122-3126 (07 01 2016) ISSN: 1464-3405 [Electronic] England
• PMID: 27177826 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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