The reductive activation of the antitumor drug RH1 to its semiquinone free radical by NADPH cytochrome P450 reductase and by HCT116 human colon cancer cells.
RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone), which is currently in clinical trials, is a diaziridinyl benzoquinone bioreductive anticancer drug that was designed to be activated by the obligate two-electron reductive enzyme NAD(P)H quinone oxidoreductase 1 (NQO1). In this electron paramagnetic resonance (EPR) study we showed that RH1 was reductively activated by the one-electron reductive enzyme NADPH cytochrome P450 reductase and by a suspension of HCT116 human colon cancer cells to yield a semiquinone free radical. As shown by EPR spin trapping experiments RH1 was reductively activated by cytochrome P450 reductase and underwent redox cycling to produce damaging hydroxyl radicals in reactions that were both H2O2- and iron-dependent. Thus, reductive activation by cytochrome P450 reductase or other reductases to produce a semiquinone that can redox cycle to produce damaging hydroxyl radicals and/or DNA-reactive alkylating species may contribute to the potent cell growth inhibitory effects of RH1. These results also suggest that selection of patients for treatment with RH1 based on their expression levels of NQO1 may be problematic.
Hasinoff
Brian B
BB
Faculty of Pharmacy, University of Manitoba, 50 Sifton Road, Winnipeg, Manitoba, Canada. b_hasinoff@umanitoba.ca
Begleiter
Asher
A
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001388:Aziridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D017665:Hydroxyl Radical / Q000737:chemistry / Q000378:metabolism; D007501:Iron / Q000737:chemistry; D015394:Molecular Structure; D009251:NADPH-Ferrihemoprotein Reductase / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D011809:Quinones / Q000737:chemistry* / Q000378:metabolism
C117776:2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone; D000970:Antineoplastic Agents; D001388:Aziridines; D016227:Benzoquinones; D011809:Quinones; D017665:Hydroxyl Radical; D006861:Hydrogen Peroxide; D007501:Iron; D009251:NADPH-Ferrihemoprotein Reductase