Identification of 3′-Methoxy-4′-nitroflavone as a Pure Aryl Hydrocarbon (Ah) Receptor Antagonist and Evidence for More Than One Form of the Nuclear Ah Receptor in MCF-7 Human Breast Cancer Cells

Lü, Yi; Santostefano, Michael J.; Cunningham, Bernadette; Threadgill, Michael D.; Safe, Stephen

doi:10.1006/abbi.1995.1062

Cited by 94 publications

(47 citation statements)

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“…CYP1A1 and CYP1A2 protein expression and catalytic activities are induced in the liver and other tissues by some of those same substrates (Eaton et al, 1995). In particular, flavonoids have been reported to bind to the Ah receptor involved in CYP1A isoform induction, leading to increased synthesis of CYP1A1 and CYP1A2 (Huang et al, 1981;Lu et al, 1995Lu et al, , 1996. In addition, P450s are involved in enzymatic activation of a number of antitumor agents in the liver (e.g., cyclophosphamide, dacarbazine, and trans-retinoic acid), lending plausibility to the idea that a cytotoxic flavonoid might induce the P450s that metabolize it to active species.…”

Section: Af (mentioning

confidence: 99%

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

et al. 2002

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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 ␣-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. AF (Fig.

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Section: Af (mentioning

confidence: 99%

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

et al. 2002

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“…These include partial agonists, such as 6-methy1-1,3,8-trichlorodibenzo-p-dioxin and a-naphthoflavone (Blank et al 1987;Astroff et al 1988;Merchant et al 1992;Santostefano et al 1992), and antagonists, including several substituted flavones (Lu et al 1995;Reiners et al 1998;Ciolino et al 1999;Henry et al 1999) and di-artha substituted polychlorinated biphenyls (PCBs) (Biegel et al 1989;Aarts et al 1995). In some instances AHR binding affinities and/or response inhibition IC50s were determined, but intrinsic efficacies of these ligands were not considered.…”

Section: Levels Of This Enzyme May Be Quantified By Immunoassay or Bymentioning

confidence: 99%

Mechanisms of action for aryl hydrocarbon receptor ligands in the PLHC-1 cell line

Hestermann¹

1999

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“…This result confirms the functional importance of XRE-3 in AhRR gene regulation. To confirm that the 3-MC induced luciferase expression is mediated by the activated AhR, AhR activity was pharmaceutically blocked by cotreatment of the transfected cells with the specific AhR antagonist MNF (Lu et al, 1995). In presence of MNF, the 3-MC-induced reporter gene activity was reduced to the level of solvent control (Fig.…”

Section: Identification Of Functional Xre Sites In the Human Ahrrmentioning

confidence: 99%

Analysis of the Transcriptional Regulation and Molecular Function of the Aryl Hydrocarbon Receptor Repressor in Human Cell Lines

Haarmann‐Stemmann¹,

Bothe²,

Kohli³

et al. 2007

Drug Metab Dispos

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Identification of 3′-Methoxy-4′-nitroflavone as a Pure Aryl Hydrocarbon (Ah) Receptor Antagonist and Evidence for More Than One Form of the Nuclear Ah Receptor in MCF-7 Human Breast Cancer Cells

Cited by 94 publications

References 0 publications

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

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

Mechanisms of action for aryl hydrocarbon receptor ligands in the PLHC-1 cell line

Analysis of the Transcriptional Regulation and Molecular Function of the Aryl Hydrocarbon Receptor Repressor in Human Cell Lines

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