title: 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.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, United States.
authors.forename: Laureen C
authors.initials: LC
authors.lastname: Colis
authors.affiliation: 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.
authors.forename: Seth B
authors.initials: SB
authors.lastname: Herzon
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005449:Fluorenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020014:K562 Cells; D015394:Molecular Structure; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D000095602:Angucyclines and Angucyclinones
chemical_list: D005449:Fluorenes; D011719:Pyrazines; D013450:Sulfones; C560580:3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide; C433842:lomaiviticin A; D000095602:Angucyclines and Angucyclinones
keywords: Cancer; Chemotherapy; DNA; Lomaiviticin; Natural product; Synergism