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Molecular Pharmacology

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Research ArticleArticle

Reversal of Physiological Stress-Induced Resistance to Topoisomerase II Inhibitors Using an Inducible Phosphorylation Site-Deficient Mutant of IκBα

Lori M. Brandes, Z. Ping Lin, Steven R. Patierno and Katherine A. Kennedy
Molecular Pharmacology September 2001, 60 (3) 559-567;
Lori M. Brandes
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Z. Ping Lin
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Steven R. Patierno
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Katherine A. Kennedy
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Abstract

Physiological stress conditions associated with the tumor microenvironment play a role in resistance to anticancer therapy. In this study, treatment of EMT6 mouse mammary tumor cells with hypoxia or the chemical stress agents brefeldin A (BFA) or okadaic acid (OA) causes the development of resistance to the topoisomerase II inhibitor etoposide. The mechanism of physiological stress-induced drug resistance may involve the activation of stress-responsive proteins and transcription factors. Our previous work shows that treatment with BFA or OA causes activation of the nuclear transcription factor NF-κB. Pretreatment with the proteasome inhibitor carbobenzyoxyl-leucinyl-leucinyl-leucinal inhibits stress-induced NF-κB activation and reverses BFA-induced drug resistance. To test whether NF-κB specifically mediates stress-induced drug resistance, an inducible phosphorylation site-deficient mutant of IκBα (IκBαM, S32/36A) was introduced into EMT6 cells. In this study, we show that IκBαM expression inhibits stress-induced NF-κB activation and prevents BFA-, hypoxia-, and OA-induced resistance to etoposide. These results indicate that NF-κB activation mediates both chemical and physiological drug resistance to etoposide. Furthermore, they imply that coadministration of agents that inhibit NF-κB may enhance the efficacy of topoisomerase II inhibitors in clinical cancer chemotherapy.

Footnotes

  • ↵1 Current address: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.

  • This work was supported in part by Army Breast Cancer Initiative Award #99–1-9186 (to K.A.K.) and by a faculty research enhancement award from the George Washington University Medical Center (to K.A.K.).

  • Abbreviations:
    ER
    endoplasmic reticulum
    EOR
    endoplasmic reticulum-overload response
    NF-κB
    nuclear factor-κB
    BFA
    brefeldin A
    OA
    okadaic acid
    MG-132
    carbobenzyoxyl-leucinyl-leucinyl-leucinal
    EMSA
    electrophoretic mobility shift assay
    HA
    hemagglutinin
    IκBαM
    S32/36A mutant inhibitory nuclear factor-κB protein α
    VCT
    vector lacking IκBαM insert
    TBST
    Tris-buffered saline/Tween 20
    BSA
    bovine serum albumin
    ANOVA
    analysis of variance
    UPR
    unfolded protein response
    • Received March 2, 2001.
    • Accepted May 22, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (3)
Molecular Pharmacology
Vol. 60, Issue 3
1 Sep 2001
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Research ArticleArticle

Reversal of Physiological Stress-Induced Resistance to Topoisomerase II Inhibitors Using an Inducible Phosphorylation Site-Deficient Mutant of IκBα

Lori M. Brandes, Z. Ping Lin, Steven R. Patierno and Katherine A. Kennedy
Molecular Pharmacology September 1, 2001, 60 (3) 559-567;

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Research ArticleArticle

Reversal of Physiological Stress-Induced Resistance to Topoisomerase II Inhibitors Using an Inducible Phosphorylation Site-Deficient Mutant of IκBα

Lori M. Brandes, Z. Ping Lin, Steven R. Patierno and Katherine A. Kennedy
Molecular Pharmacology September 1, 2001, 60 (3) 559-567;
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