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

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.

• Authors: Laureen C Colis, Christina M Woo, Denise C Hegan, Zhenwu Li, Peter M Glazer, Seth B Herzon
• Journal: Nature chemistry (Nat Chem) Vol. 6 Issue 6 Pg. 504-10 (Jun 2014) ISSN: 1755-4349 [Electronic] England
• PMID: 24848236 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Fluorenes
• lomaiviticin A

Topics

• 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, genetics, pathology)
• Tumor Cells, Cultured