1. Synergistic potentiation of (−)-lomaiviticin A cytotoxicity by the ATR inhibitor VE-821.
- Author
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Colis, Laureen C. and Herzon, Seth B.
- Subjects
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DRUG synergism , *BACTERIAL metabolites , *SERINE/THREONINE kinases , *ENZYME inhibitors , *APOPTOSIS , *ANTINEOPLASTIC agents - 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 0.5 nM 1 or 10 μM 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 48 h, 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. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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