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Research ArticleCellular and Molecular

Aryl Hydrocarbon Receptor (AHR)-Active Pharmaceuticals Are Selective AHR Modulators in MDA-MB-468 and BT474 Breast Cancer Cells

Un-Ho Jin, Syng-ook Lee and Stephen Safe
Journal of Pharmacology and Experimental Therapeutics November 2012, 343 (2) 333-341; DOI: https://doi.org/10.1124/jpet.112.195339
Un-Ho Jin
Institute of Biosciences and Technology, Texas A&M Health Sciences Center, Houston, Texas (U.-H.J., S.L., S.S.); and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (S.S.)
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Syng-ook Lee
Institute of Biosciences and Technology, Texas A&M Health Sciences Center, Houston, Texas (U.-H.J., S.L., S.S.); and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (S.S.)
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Stephen Safe
Institute of Biosciences and Technology, Texas A&M Health Sciences Center, Houston, Texas (U.-H.J., S.L., S.S.); and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (S.S.)
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Abstract

Leflunomide, flutamide, nimodipine, mexiletine, sulindac, tranilast, 4-hydroxytamoxifen, and omeprazole are pharmaceuticals previously characterized as aryl hydrocarbon receptor (AHR) agonists in various cell lines and animal models. In this study, the eight AHR-active pharmaceuticals were investigated in highly aggressive aryl hydrocarbon (Ah)-responsive BT474 and MDA-MB-468 breast cancer cell lines, and their effects on AHR protein, CYP1A1 (protein and mRNA), CYP1B1 (mRNA), and cell migration were determined. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was used as a positive control. The AHR agonist activities of the pharmaceuticals depended on structure, response, and cell context. Most compounds induced one or more AHR-mediated responses in BT474 cells, whereas in Ah-responsive MDA-MB-468 cells effects of the AHR-active pharmaceuticals were highly variable. 4-Hydroxytamoxifen, mexiletine, and tranilast did not induce CYP1A1 in MDA-MB-468 cells; moreover, in combination with TCDD, mexiletine was a potent AHR antagonist, tranilast was a partial antagonist, and 4-hydroxytamoxifen also exhibited some AHR antagonist activity. Omeprazole and, to a lesser extent, sulindac and leflunomide were full and partial AHR agonists, respectively, in both breast cancer cell lines. These data indicate that the AHR-active pharmaceuticals are selective AHR modulators, and applications of these drugs for targeting the AHR must be confirmed by studies using the most relevant cell context.

Footnotes

  • This work was supported by the National Institutes of Health National Cancer Institute [Grant R01CA142697] and Texas AgriLife.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.195339.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    AHR
    aryl hydrocarbon receptor
    SAhRM
    selective AHR modulator
    Ah
    aryl hydrocarbon
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    DRE
    dioxin responsive element
    MCDF
    6-methyl-1,3,8-trichlorodibenzofuran
    ER
    estrogen receptor
    ErbB2
    epidermal growth factor receptor 2
    DMEM
    Dulbecco's modified Eagle's medium
    FBS
    fetal bovine serum
    ChIP
    chromatin immunoprecipitation
    MTT
    3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide
    PCR
    polymerase chain reaction
    DMSO
    dimethyl sulfoxide
    TBP
    TATA-binding protein.

  • Received April 6, 2012.
  • Accepted August 8, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
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Research ArticleCellular and Molecular

AHR-Active Pharmaceuticals Are SAhRMs

Un-Ho Jin, Syng-ook Lee and Stephen Safe
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 333-341; DOI: https://doi.org/10.1124/jpet.112.195339

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Research ArticleCellular and Molecular

AHR-Active Pharmaceuticals Are SAhRMs

Un-Ho Jin, Syng-ook Lee and Stephen Safe
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 333-341; DOI: https://doi.org/10.1124/jpet.112.195339
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