Open AccessIndoloquinone EO9: DNA interstrand cross-linking upon reduction by DT-diaphorase or xanthine oxidase
Author(s) -
Marc Maliepaard,
A. Wolfs,
S. E. Groot,
N. J. de Mol,
Lambert H.M. Janssen
Publication year - 1995
Publication title -
british journal of cancer
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 2.833
H-Index - 236
eISSN - 1532-1827
pISSN - 0007-0920
DOI - 10.1038/bjc.1995.161
Subject(s) - xanthine oxidase , xanthine , dna , biochemistry , enzyme , chemistry , dicoumarol , oxidase test , microbiology and biotechnology , biology , nad+ kinase
We report DNA interstrand cross-linking caused by the anti-tumour indoloquinone EO9 following reductive activation with purified rat liver DT-diaphorase or xanthine oxidase. Reduction was a necessary event for cross-linking to occur. DNA cross-link formation by EO9 following DT-diaphorase reduction was completely inhibited by addition 10 microM dicoumarol, whereas only a minor effect of dicoumarol on xanthine oxidase-mediated DNA cross-linking by EO9 was observed. DNA cross-linking was pH dependent, with increasing cross-link formation from pH 5.5 to 7.0 for both DT-diaphorase and xanthine oxidase mediated reactions. Also, conversion of EO9 upon reduction was pH dependent. However, in contrast to DNA cross-linking, conversion rates of EO9 decreased at higher pH. EO9 was shown to be more efficient in DNA cross-linking than mitomycin C under identical conditions, using both DT-diaphorase and xanthine oxidase reductive activation at pH 5.5 and 7.0. This study indicates that the anti-tumour activity of EO9 may be at least partly mediated by interstrand DNA cross-link formation, and that various reducing enzymes may be important for activation of EO9 in vitro and in vivo.