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Molecular Pharmacology

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Research ArticleArticle

The Use of a Novel Taxane-Based P-Glycoprotein Inhibitor to Identify Mutations That Alter the Interaction of the Protein with Paclitaxel

Donald J. Gruol, Josh Bernd, Alba E. Phippard, Iwao Ojima and Ralph J. Bernacki
Molecular Pharmacology July 2001, 60 (1) 104-113; DOI: https://doi.org/10.1124/mol.60.1.104
Donald J. Gruol
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Josh Bernd
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Alba E. Phippard
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Iwao Ojima
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Ralph J. Bernacki
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Abstract

Murine thymoma cell lines expressing mutated forms of themdr1b P-glycoprotein were isolated using a novel taxane-based P-glycoprotein inhibitor tRA-96023 (SB-RA-31012). The selection strategy required resistance to a combination of tRA-96023 and colchicine. Five mutations were identified (N350I, I862F, L865F, L868W, and A933T) that reduce the capacity of tRA-96023 to inhibit P-glycoprotein-dependent drug resistance. These mutations also result in a loss of paclitaxel resistance ranging from 47 to 100%. Four mutations are located in the second half of the protein, within or near the proposed transmembrane segment (TMS) 10–11 regions. The fifth mutation (N350I) is within the first half of the protein, proximal (cytoplasmic) to TMS 6. The variant cell line expressing the L868W mutation was subjected to a second round of selection involving tRA-96023 and the toxic drug puromycin. This resulted in the isolation of a cell line expressing a P-glycoprotein with a double mutation. The additional mutation (N988D) is located within TMS 12 and conveys further decreases in resistance to paclitaxel and the capacity of tRA-96023 to inhibit drug resistance. Taken together, the results indicate a significant contribution by the TMS 10–12 portion of the protein to the recognition and transport of taxanes and give evidence that the cytoplasmic region proximal to TMS 6 also plays a role in taxane interactions with P-glycoproteins. Interestingly, mutations within TMS 6 and 12 were found to cause a partial loss of PSC-833 inhibitor activity, suggesting that these regions participate in the interactions with cyclosporin and its derivatives.

  • Abbreviations

    TMS
    transmembrane segment
    5βPodo
    5β-pregnane-17ol-3,20-dione
    PCR
    polymerase chain reaction
    Pgp
    P-glycoprotein
    • Received November 11, 2000.
    • Accepted March 14, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Molecular Pharmacology: 60 (1)
    Molecular Pharmacology
    Vol. 60, Issue 1
    1 Jul 2001
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    Research ArticleArticle

    The Use of a Novel Taxane-Based P-Glycoprotein Inhibitor to Identify Mutations That Alter the Interaction of the Protein with Paclitaxel

    Donald J. Gruol, Josh Bernd, Alba E. Phippard, Iwao Ojima and Ralph J. Bernacki
    Molecular Pharmacology July 1, 2001, 60 (1) 104-113; DOI: https://doi.org/10.1124/mol.60.1.104

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    Research ArticleArticle

    The Use of a Novel Taxane-Based P-Glycoprotein Inhibitor to Identify Mutations That Alter the Interaction of the Protein with Paclitaxel

    Donald J. Gruol, Josh Bernd, Alba E. Phippard, Iwao Ojima and Ralph J. Bernacki
    Molecular Pharmacology July 1, 2001, 60 (1) 104-113; DOI: https://doi.org/10.1124/mol.60.1.104
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