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

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

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  • 1Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
  • 2Departments of Therapeutic Radiology and Genetics, Yale School of Medicine, New Haven, Connecticut 06520, USA.

Abstract

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.

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PMID:
24848236
[PubMed - indexed for MEDLINE]
PMCID:
PMC4090708
Free PMC Article
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