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, Matthew M. Ames

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Abstract

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 in vivo antiproliferative activity against a number of human tumor cell lines and with a unique pattern of antiproliferative activity in the National Cancer Institute tumor cell line screen. AF was extensively metabolized by cytochrome P450 (P450) 1A1 and 1A2 to several metabolites, one of which was identified by mass spectrometry as a potentially reactive hydroxylamine. Radiolabeled AF was converted by rat and human microsomes, by recombinant CYP1A1 and CYP1A2, and by sensitive human tumor cell lines to species that covalently bound macromolecules. Treatment of sensitive human MCF7 cells with AF resulted in increased CYP1A1 mRNA and CYP1A1/1A2 protein followed by covalent binding of an AF metabolite to DNA, phosphorylation and stabilization of p53, and increased expression of the p53 transcriptional target p21. Covalent binding of the AF metabolite was increased by pretreatment with the CYP1A inducer 3-methylcholanthrene and decreased by coincubation with the CYP1A inhibitor α-naphthoflavone. In contrast, induction of CYP1A1 and covalent binding of the AF metabolite did not occur in AF-resistant M14-MEL cells. These observations suggest that AF is uniquely able to induce its own metabolic activation via CYP1A1/1A2 in duction to cytotoxic DNA-damaging species directly in tumor cells. AF, and possibly other agents, may offer a treatment strategy for tumors responsive to CYP1A1/1A2 induction, such as breast, ovarian, and renal cancers.

Original languageEnglish (US)
Pages (from-to)143-153
Number of pages11
JournalMolecular Pharmacology
Volume62
Issue number1
DOIs
StatePublished - 2002

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aminoflavone
Cytochrome P-450 CYP1A2
Cytochrome P-450 CYP1A1
Antineoplastic Agents
Tumor Cell Line
Neoplasms
flavone
Hydroxylamine
Methylcholanthrene
National Cancer Institute (U.S.)
Kidney Neoplasms
DNA
MCF-7 Cells
Microsomes
Ovarian Neoplasms
Cytochrome P-450 Enzyme System
Mass Spectrometry
Phosphorylation
Breast Neoplasms

ASJC Scopus subject areas

  • Pharmacology

Cite this

Activation of the antitumor agent aminoflavone (NSC 686288) is mediated by induction of tumor cell cytochrome P450 1A1/1A2. / Kuffel, Mary J.; Schroeder, Jennifer C.; Pobst, Lori J.; Naylor, Stephen; Reid, Joel M; Kaufmann, Scott H; Ames, Matthew M.

In: Molecular Pharmacology, Vol. 62, No. 1, 2002, p. 143-153.

Research output: Contribution to journalArticle

Kuffel, Mary J. ; Schroeder, Jennifer C. ; Pobst, Lori J. ; Naylor, Stephen ; Reid, Joel M ; Kaufmann, Scott H ; Ames, Matthew M. / Activation of the antitumor agent aminoflavone (NSC 686288) is mediated by induction of tumor cell cytochrome P450 1A1/1A2. In: Molecular Pharmacology. 2002 ; Vol. 62, No. 1. pp. 143-153.
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abstract = "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 in vivo antiproliferative activity against a number of human tumor cell lines and with a unique pattern of antiproliferative activity in the National Cancer Institute tumor cell line screen. AF was extensively metabolized by cytochrome P450 (P450) 1A1 and 1A2 to several metabolites, one of which was identified by mass spectrometry as a potentially reactive hydroxylamine. Radiolabeled AF was converted by rat and human microsomes, by recombinant CYP1A1 and CYP1A2, and by sensitive human tumor cell lines to species that covalently bound macromolecules. Treatment of sensitive human MCF7 cells with AF resulted in increased CYP1A1 mRNA and CYP1A1/1A2 protein followed by covalent binding of an AF metabolite to DNA, phosphorylation and stabilization of p53, and increased expression of the p53 transcriptional target p21. Covalent binding of the AF metabolite was increased by pretreatment with the CYP1A inducer 3-methylcholanthrene and decreased by coincubation with the CYP1A inhibitor α-naphthoflavone. In contrast, induction of CYP1A1 and covalent binding of the AF metabolite did not occur in AF-resistant M14-MEL cells. These observations suggest that AF is uniquely able to induce its own metabolic activation via CYP1A1/1A2 in duction to cytotoxic DNA-damaging species directly in tumor cells. AF, and possibly other agents, may offer a treatment strategy for tumors responsive to CYP1A1/1A2 induction, such as breast, ovarian, and renal cancers.",
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