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Research ArticleArticle

Polygamain, a New Microtubule Depolymerizing Agent That Occupies a Unique Pharmacophore in the Colchicine Site

R. M. Hartley, J. Peng, G. A. Fest, S. Dakshanamurthy, D. E. Frantz, M. L. Brown and S. L. Mooberry
Molecular Pharmacology March 2012, 81 (3) 431-439; DOI: https://doi.org/10.1124/mol.111.075838
R. M. Hartley
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J. Peng
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G. A. Fest
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S. Dakshanamurthy
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D. E. Frantz
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M. L. Brown
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S. L. Mooberry
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Abstract

Bioassay-guided fractionation was used to isolate the lignan polygamain as the microtubule-active constituent in the crude extract of the Mountain torchwood, Amyris madrensis. Similar to the effects of the crude plant extract, polygamain caused dose-dependent loss of cellular microtubules and the formation of aberrant mitotic spindles that led to G2/M arrest. Polygamain has potent antiproliferative activities against a wide range of cancer cell lines, with an average IC50 of 52.7 nM. Clonogenic studies indicate that polygamain effectively inhibits PC-3 colony formation and has excellent cellular persistence after washout. In addition, polygamain is able to circumvent two clinically relevant mechanisms of drug resistance, the expression of P-glycoprotein and the βIII isotype of tubulin. Studies with purified tubulin show that polygamain inhibits the rate and extent of purified tubulin assembly and displaces colchicine, indicating a direct interaction of polygamain within the colchicine binding site on tubulin. Polygamain has structural similarities to podophyllotoxin, and molecular modeling simulations were conducted to identify the potential orientations of these compounds within the colchicine binding site. These studies suggest that the benzodioxole group of polygamain occupies space similar to the trimethoxyphenyl group of podophyllotoxin but with distinct interactions within the hydrophobic pocket. Our results identify polygamain as a new microtubule destabilizer that seems to occupy a unique pharmacophore within the colchicine site of tubulin. This new pharmacophore will be used to design new colchicine site compounds that might provide advantages over the current agents.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the Department of Defense Prostate Program [Grant W81XWH-08-1-0395]; the National Institutes of Health National Institute of Dental and Craniofacial Research COSTAR Program [Grant T32-DE14318]; and the National Institutes of Health National Cancer Institute [Grant P30-CA054174] (to the Cancer Therapy & Research Center at the University of Texas Health Science Center at San Antonio). We acknowledge the use of the CTRC Flow Cytometry and Macromolecular Structure shared resources.

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

    http://dx.doi.org/10.1124/mol.111.075838.

  • ABBREVIATIONS:

    CA
    combretastatin
    FBS
    fetal bovine serum
    Pgp
    P-glycoprotein
    DMSO
    dimethyl sulfoxide
    WT
    wild-type
    βIII
    βIII tubulin
    Rr
    relative resistance.

  • Received September 16, 2011.
  • Accepted December 14, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Research ArticleArticle

Polygamain, New Microtubule Depolymerizer

R. M. Hartley, J. Peng, G. A. Fest, S. Dakshanamurthy, D. E. Frantz, M. L. Brown and S. L. Mooberry
Molecular Pharmacology March 1, 2012, 81 (3) 431-439; DOI: https://doi.org/10.1124/mol.111.075838

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Research ArticleArticle

Polygamain, New Microtubule Depolymerizer

R. M. Hartley, J. Peng, G. A. Fest, S. Dakshanamurthy, D. E. Frantz, M. L. Brown and S. L. Mooberry
Molecular Pharmacology March 1, 2012, 81 (3) 431-439; DOI: https://doi.org/10.1124/mol.111.075838
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