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Review ArticleMinireview

Drug Efflux Transporters and Multidrug Resistance in Acute Leukemia: Therapeutic Impact and Novel Approaches to Mediation

Cindy Q. Xia and Peter G. Smith
Molecular Pharmacology December 2012, 82 (6) 1008-1021; DOI: https://doi.org/10.1124/mol.112.079129
Cindy Q. Xia
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts
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Peter G. Smith
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts
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Abstract

Multidrug resistance (MDR), which is mediated by multiple drug efflux ATP-binding cassette (ABC) transporters, is a critical issue in the treatment of acute leukemia, with permeability glycoprotein (P-gp), multidrug resistance-associated protein 1, and breast cancer resistance protein (i.e., ABCG2) consistently being shown to be key effectors of MDR in cell line studies. Studies have demonstrated that intrinsic MDR can arise as a result of specific gene expression profiles and that drug-induced overexpression of P-gp and other MDR proteins can result in acquired resistance, with multiple ABC transporters having been shown to be overexpressed in cell lines selected for resistance to multiple drugs used to treat acute leukemia. Furthermore, numerous anticancer drugs, including agents commonly used for the treatment of acute leukemia (e.g., doxorubicin, vincristine, mitoxantrone, and methotrexate), have been shown to be P-gp substrates or to be susceptible to efflux mediated by other MDR proteins, and multiple clinical studies have demonstrated associations between P-gp or other MDR protein expression and responses to therapy or survival rates in acute leukemia. Here we review the importance of MDR in cancer, with a focus on acute leukemia, and we highlight the need for rapid accurate assessment of MDR status for optimal treatment selection. We also address the latest research on overcoming MDR, from inhibition of P-gp and other MDR proteins through various approaches (including direct antagonism and gene silencing) to the design of novel agents or novel delivery systems for existing therapeutic agents, to evade cellular efflux.

Footnotes

  • This work was supported by Millennium Pharmaceuticals, Inc.

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

    http://dx.doi.org/10.1124/mol.112.079129.

  • ABBREVIATIONS:

    MDR
    multidrug resistance
    ABC
    ATP-binding cassette
    ALL
    acute lymphoblastic leukemia
    AML
    acute myeloid leukemia
    BCRP
    breast cancer resistance protein
    COX
    cyclooxygenase
    CR
    complete remission
    EFS
    event-free survival
    GCS
    glucosylceramide synthase
    LRP
    lung resistance protein
    MRP
    multidrug resistance-associated protein
    CML
    chronic myeloid leukemia
    ITD
    internal tandem duplication
    OS
    overall survival
    P-gp
    permeability glycoprotein
    shRNA
    short hairpin RNA
    siRNA
    small interfering RNA
    SNP
    single-nucleotide polymorphism
    RT
    reverse transcription
    PCR
    polymerase chain reaction
    hOCT1
    human organic cation transporter 1
    JC-1
    5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide
    FG020326
    (E)-methyl-3-[4-[4,5-bis(4-[isopropyl(methyl)amino]phenyl)-1H-imidazol-2-yl]phenyl]acrylate
    Genz-123346
    (1R,2R)-nonanoic acid-[2-(2′,3′-dihydrobenzo[1,4]dioxin-6′-yl)-2-hydroxy-1-pyrrolidin-1-yl-methylethyl]amide l-tartaric acid salt
    MZ3
    4-(4-bromophenyl)-2,3-dihydro-N,3-bis(3,4,5-trimethoxyphenyl)-2-oxoidmidazole-1-carboxamide.

  • Received April 5, 2012.
  • Accepted July 23, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (6)
Molecular Pharmacology
Vol. 82, Issue 6
1 Dec 2012
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Review ArticleMinireview

Efflux Transporters and Multidrug Resistance in Leukemia

Cindy Q. Xia and Peter G. Smith
Molecular Pharmacology December 1, 2012, 82 (6) 1008-1021; DOI: https://doi.org/10.1124/mol.112.079129

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Review ArticleMinireview

Efflux Transporters and Multidrug Resistance in Leukemia

Cindy Q. Xia and Peter G. Smith
Molecular Pharmacology December 1, 2012, 82 (6) 1008-1021; DOI: https://doi.org/10.1124/mol.112.079129
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