The cytotoxicity of (-)-lomaiviticin A arises from induction of double-strand breaks in DNA

Nat Chem. 2014 Jun;6(6):504-10. doi: 10.1038/nchem.1944. Epub 2014 May 11.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Proliferation / drug effects
  • DNA Breaks, Double-Stranded / drug effects*
  • Fluorenes / toxicity*
  • Fluorescent Antibody Technique
  • Humans
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / pathology*
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Fluorenes
  • lomaiviticin A