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OtherPULMONARY PHARMACOLOGY

Dehydroepiandrosterone and Analogs Inhibit DNA Binding of AP-1 and Airway Smooth Muscle Proliferation

Rustom Dashtaki, A. Richard Whorton, Thomas M. Murphy, Pasquale Chitano, William Reed and Thomas P. Kennedy
Journal of Pharmacology and Experimental Therapeutics May 1998, 285 (2) 876-883;
Rustom Dashtaki
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A. Richard Whorton
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Thomas M. Murphy
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Pasquale Chitano
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William Reed
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Thomas P. Kennedy
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Abstract

The adrenal steroid dehydroepiandrosterone (DHEA) and its analogs reduce growth of immortalized and malignant cell lines. We therefore explored their effects on the growth of airway smooth muscle, whose hyperplasia may lead to fixed airways obstruction and enhanced airways hyperresponsiveness in severe chronic asthma. DHEA and its potent analog 16α-bromoepiandrosterone dramatically reduced proliferation in primary cultures of rat tracheal smooth muscle stimulated with fetal bovine serum or platelet-derived growth factor. Growth inhibition was dose-dependent and could not be attributed to interference with glucose-6-phosphate dehydrogenase activity or cholesterol metabolism, as reported for immortalized or malignant cell lines, respectively. Expression of the early response gene c-fos remained intact, but DHEA and 16α-bromoepiandrosterone decreased DNA binding of the transcription factor activator protein-1, a later response important for expression of genes that mediate DNA synthesis and cell cycle progression. These results suggest that the nonglucocorticoid steroid DHEA and its analogs may impair activation of secondary growth response genes in a fashion analogous to that reported for glucocorticoids and that they may prove useful for treatment of asthmatic airway remodeling in the human.

Footnotes

  • Send reprint requests to: Thomas P. Kennedy, M.D., Department of Internal Medicine, Carolinas Medical Center, P.O. Box 32861, Charlotte, NC 28232.

  • ↵1 This work was supported by the Charlotte-Mecklenberg Hospital Foundation (T.K.) and in part by NIH grant HL-48376 (T.M.M).

  • Abbreviations:
    DHEA
    dehydroepiandrosterone
    DHEAS
    dehydroepiandrosterone sulfate
    16α-BrEA or BrEA
    16α-bromoepiandrosterone
    AP-1
    activator protein-1
    DMEM
    Dulbecco’s modified Eagle’s medium
    HBSS
    Hanks’ balanced salt solution
    FBS
    fetal bovine serum
    PDGF
    human platelet-derived growth factor-AA
    Tris
    Tris(hydroxymethyl)aminomethane
    MTT
    3-[4,5-dimethylthiazol]-2yl-2,5-diphenyl tetrazolium bromide
    DPBS
    Dulbecco’s modified phosphate-buffered saline without Ca2+or Mg2+
    DMSO
    dimethylsulfoxide
    G6PDH
    glucose-6-phosphate dehydrogenase
    G6P
    d-glucose-6-phosphate
    SDS
    sodium docecyl sulfate
    HRP
    horseradish peroxidase
    IgG
    immunoglobulin G
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    CEB
    cell extraction buffer
    PI
    protease inhibitors
    NP-40
    Nonidet P-40
    NEB
    nuclear extraction buffer
    MAPK
    mitogen-activated protein kinase
    TRE
    TPA-response element
    GRE
    glucocorticoid response element
    NF-κB
    nuclear factor κB
    EMSA
    electrophoretic mobility shift assay
    • Received July 28, 1997.
    • Accepted January 12, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 2
1 May 1998
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OtherPULMONARY PHARMACOLOGY

Dehydroepiandrosterone and Analogs Inhibit DNA Binding of AP-1 and Airway Smooth Muscle Proliferation

Rustom Dashtaki, A. Richard Whorton, Thomas M. Murphy, Pasquale Chitano, William Reed and Thomas P. Kennedy
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 876-883;

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OtherPULMONARY PHARMACOLOGY

Dehydroepiandrosterone and Analogs Inhibit DNA Binding of AP-1 and Airway Smooth Muscle Proliferation

Rustom Dashtaki, A. Richard Whorton, Thomas M. Murphy, Pasquale Chitano, William Reed and Thomas P. Kennedy
Journal of Pharmacology and Experimental Therapeutics May 1, 1998, 285 (2) 876-883;
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