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

Authors: Colis, Laureen C; Woo, Christina M; Hegan, Denise C; Li, Zhenwu; Glazer, Peter M; Herzon, Seth B

Published In Nat Chem, (2014 Jun)

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.

PubMed ID: 24848236

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