The cytotoxicity of (-)-lomaiviticin A arises from induction of double-strand breaks in DNA.
The metabolite (-)-lomaiviticin A, which contains two diazotetrahydrobenzo[b]fluorene (diazofluorene) functional groups, inhibits the growth of cultured human cancer cells at nanomolar-picomolar concentrations; however, the mechanism responsible for the potent cytotoxicity of this natural product is not known. Here we report that (-)-lomaiviticin A nicks and cleaves plasmid DNA by a pathway that is independent of reactive oxygen species and iron, and that the potent cytotoxicity of (-)-lomaiviticin A arises from the induction of DNA double-strand breaks (dsbs). In a plasmid cleavage assay, the ratio of single-strand breaks (ssbs) to dsbs is 5.3 ± 0.6:1. Labelling studies suggest that this cleavage occurs via a radical pathway. The structurally related isolates (-)-lomaiviticin C and (-)-kinamycin C, which contain one diazofluorene, are demonstrated to be much less effective DNA cleavage agents, thereby providing an explanation for the enhanced cytotoxicity of (-)-lomaiviticin A compared to that of other members of this family.
Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
Laureen C
LC
Colis
Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
Christina M
CM
Woo
Departments of Therapeutic Radiology and Genetics, Yale School of Medicine, New Haven, Connecticut 06520, USA.
Denise C
DC
Hegan
Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
Zhenwu
Z
Li
Departments of Therapeutic Radiology and Genetics, Yale School of Medicine, New Haven, Connecticut 06520, USA.
Peter M
PM
Glazer
Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
Seth B
SB
Herzon
D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D005449:Fluorenes / Q000633:toxicity*; D005455:Fluorescent Antibody Technique; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured; D000095602:Angucyclines and Angucyclinones
D000970:Antineoplastic Agents; D005449:Fluorenes; C433842:lomaiviticin A; D000095602:Angucyclines and Angucyclinones