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

(−)-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.

K562 cells treated with 500 pM (−)-lomaiviticin A and 10 μM of the ATR inhibitor VE-821 display pan-γH2AX staining and undergo apoptosis.Figure optionsDownload as PowerPoint slide