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

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• 作者：Laureen C. Colis^a ; Seth B. Herzon^a ; ^b ; ^{seth.herzon@yale.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ATR ; ataxia telangiectasia and Rad3-related protein ; SSB ; single-strand break ; DSB ; double-strand break ; PI3KK ; phosphatidylinositol 3-kinase-related kinase ; ATM ; ataxia telangiectasia mutated ; DNA-PKcs ; DNA-dependent protein kinase catalytic subunit ; BRCA2 ; breast cancer type 2 ; PTEN ; phosphatase and tensin homolog ; KU80 ; Ku autoantigen protein p80 ; NHEJ ; non-homologous end joining ; HR ; homologous recombination ; IR ; ionizing radiation ; PARP-1 ; poly(ADP-ribose) polymerase-1 ; PARP-2 ; poly(ADP-rib
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 July 2016
• 年：2016
• 卷：26
• 期：13
• 页码：3122-3126
• 全文大小：911 K

文摘

(−)-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.