Activation of the Antitumor Agent Aminoflavone (NSC 686288) Is Mediated by Induction of Tumor Cell Cytochrome P450 1A1/1A2

doi:10.1124/mol.62.1.143

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Vol. 62, Issue 1, 143-153, July 2002

Activation of the Antitumor Agent Aminoflavone (NSC 686288) Is Mediated by Induction of Tumor Cell Cytochrome P450 1A1/1A2

Mary J. Kuffel, Jennifer C. Schroeder, Lori J. Pobst, Stephen Naylor, Joel M. Reid, Scott H. Kaufmann, and Matthew M. Ames

Departments of Oncology (M.J.K., J.M.R., S.H.K., M.M.A.) and Molecular Pharmacology and Experimental Therapeutics (J.C.S., L.J.P., S.N., S.H.K., M.M.A.), Mayo Clinic, Rochester, Minnesota

The present studies were performed to elucidate the mechanism of cytotoxicity of the aminoflavone analog (5-amino-2,3-fluorophenyl)-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one(AF; NSC 686288), a novel flavone with potent in vitro and invivo antiproliferative activity against a number of human tumorcell lines and with a unique pattern of antiproliferative activityin the National Cancer Institute tumor cell line screen. AF wasextensively metabolized by cytochrome P450 (P450) 1A1 and 1A2to several metabolites, one of which was identified by mass spectrometryas a potentially reactive hydroxylamine. Radiolabeled AF was convertedby rat and human microsomes, by recombinant CYP1A1 and CYP1A2,and by sensitive human tumor cell lines to species that covalentlybound macromolecules. Treatment of sensitive human MCF7 cellswith AF resulted in increased CYP1A1 mRNA and CYP1A1/1A2 proteinfollowed by covalent binding of an AF metabolite to DNA, phosphorylationand stabilization of p53, and increased expression of the p53transcriptional target p21. Covalent binding of the AF metabolitewas increased by pretreatment with the CYP1A inducer 3-methylcholanthreneand decreased by coincubation with the CYP1A inhibitor $alpha$ -naphthoflavone.In contrast, induction of CYP1A1 and covalent binding of the AFmetabolite did not occur in AF-resistant M14-MEL cells. Theseobservations suggest that AF is uniquely able to induce its ownmetabolic activation via CYP1A1/1A2 in duction to cytotoxic DNA-damagingspecies directly in tumor cells. AF, and possibly other agents,may offer a treatment strategy for tumors responsive to CYP1A1/1A2induction, such as breast, ovarian, and renalcancers.

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