Unbound MEDLINE

The proteasome inhibitor bortezomib reverses P-glycoprotein-mediated leukemia multi-drug resistance through the NF-kappaB pathway.

Abstract

Multi-drug resistance (MDR) is one of the obstacles for leukemia therapy, the major cause is an overexpression of P-glycoprotein (P-gp) leading to increased drug efflux. We investigated the reversion of multi-drug resistance and the possible mechanism by which the proteasome inhibitor bortezomib affects the expression of the multi-drug resistance gene mdrl in the K562/DNR cell line. The drug resistance of the cells and the cellular toxicity of bortezomib were confirmed by MTT. Intracellular drug concentrations and cell apoptosis were detected by flow cytometry. The expression of mdrl mRNA was examined by fluorescence quantitative PCR. The expression levels of nuclear factor-kappa B (NF-kappaB), inhibitor of NF-kappaB (IkappaB) and P-gp were detected by western blotting, and NF-kappaB activity was detected by ELISA. DNR-induced apoptosis increased in a dose-dependent manner after adding bortezomib. Bortezomib decreased IkappaB degradation, decreased NF-kappaB and NF-kappaB p65 activity, reduced P-gp/mdr1 mRNA expression, and increased the intracellular DNR concentration in K562/DNR cells in vitro. The bortezomib reversed leukemic multi-drug resistance in a dose-dependent manner as the result of decreasing IkappaB degradation, thus preventing the translocation of NF-kappaB into the nucleus and leading the down-regulation of mdr1 and a reduction in P-gp expression. Therefore, the intracellular drug concentration increased, and then apoptosis was induced.

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  • Publisher Full Text
  • Authors

    Wang H, Wang X, Li Y, Liao A, Fu B, Pan H, Liu Z, Yang W

    Source

    Die Pharmazie 67:2 2012 Feb pg 187-92

    MeSH

    Antineoplastic Agents
    Apoptosis
    Boronic Acids
    Cell Survival
    Coloring Agents
    Drug Resistance, Neoplasm
    Enzyme-Linked Immunosorbent Assay
    Flow Cytometry
    Humans
    I-kappa B Proteins
    Indicators and Reagents
    K562 Cells
    NF-kappa B
    P-Glycoprotein
    Polymerase Chain Reaction
    Proteasome Inhibitors
    Pyrazines
    RNA, Messenger
    Signal Transduction
    Tetrazolium Salts
    Thiazoles
    Transcription Factor RelA

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22512091