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

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

Author information

1
Department of Chemistry, Yale University, New Haven, CT 06520, United States.
2
Department of Chemistry, Yale University, New Haven, CT 06520, United States; Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520, United States. Electronic address: seth.herzon@yale.edu.

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

PMID:
27177826
PMCID:
PMC4899226
DOI:
10.1016/j.bmcl.2016.04.090
[Indexed for MEDLINE]
Free PMC Article

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