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Molecular Pharmacology

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Research ArticleArticle

The Histone Deacetylase Inhibitor MGCD0103 Has Both Deacetylase and Microtubule Inhibitory Activity

KeeMing Chia, Heather Beamish, Kaneez Jafferi and Brian Gabrielli
Molecular Pharmacology September 2010, 78 (3) 436-443; DOI: https://doi.org/10.1124/mol.110.065169
KeeMing Chia
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Heather Beamish
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Kaneez Jafferi
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Brian Gabrielli
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Abstract

Histone deacetylase inhibitors (HDACis) are currently in trial or are in clinical use for the treatment of a number of tumor types. The clinical efficacy of HDACis can be partly attributed to the modulation of the cell cycle by the HDACis. Here, we have examined the effects of N-(2-aminophenyl)-4-((4-pyridin-3-ylpyrimidin-2-ylamino)methyl)benzamide (MGCD0103), a class I-selective histone deacetylase inhibitor, on the cell cycle and cell killing. Surprisingly, MGCD0103 treatment failed to initiate a G1-phase arrest but caused marked accumulation of cells in G2/M at 6 and 12 h after treatment and was cytotoxic 24 h after treatment. These cell cycle effects were considerably distinct from the effects of suberic bishydroxamic acid, a representative of the pan-isoform HDACi used in this study. MGCD0103 shared the ability of the pan-isoform HDACi to trigger defective mitosis and promote mitotic slippage. Likewise, it also specifically targeted tumor cells and was nontoxic to normal nontransformed cells. However, MGDC0103 also seemed to disrupt normal microtubule spindle formation, whereas HDACis generally have only a minor effect on spindle formation. The effect of MGCD0103 on spindle formation was shown to be a consequence of microtubule destabilization. This is the first example of an HDACi with microtubule destabilizing activity, and the combined effects of this drug have advantages for its therapeutic use.

Footnotes

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

  • This work was supported by a Grant from Cancer Council Queensland; and a National Health and Medical Research Council Senior Research Fellowship.

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

    doi:10.1124/mol.110.065169.

  • ABBREVIATIONS:

    HDACis
    histone deacetylase inhibitors
    HDAC
    histone deacetylase
    SBHA
    suberic bishydroxamic acid
    MGCD0103
    N-(2- aminophenyl)-4-((4-pyridin-3-ylpyrimidin-2-ylamino)methyl)benzamide
    MS-275
    N-(2-aminophenyl)-4-[N-(pyridine-3-ylmethoxy-carbonyl) aminomethyl]benzamide
    DMSO
    dimethyl sulfoxide
    PBS
    phosphate-buffered saline
    FACS
    fluorescence-activated cell sorting
    PARP
    poly(ADP-ribose) polymerase
    NFF
    neonatal foreskin fibroblast
    siRNA
    small interfering RNA.

  • Received March 29, 2010.
  • Accepted June 7, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (3)
Molecular Pharmacology
Vol. 78, Issue 3
1 Sep 2010
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Research ArticleArticle

The Histone Deacetylase Inhibitor MGCD0103 Has Both Deacetylase and Microtubule Inhibitory Activity

KeeMing Chia, Heather Beamish, Kaneez Jafferi and Brian Gabrielli
Molecular Pharmacology September 1, 2010, 78 (3) 436-443; DOI: https://doi.org/10.1124/mol.110.065169

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Research ArticleArticle

The Histone Deacetylase Inhibitor MGCD0103 Has Both Deacetylase and Microtubule Inhibitory Activity

KeeMing Chia, Heather Beamish, Kaneez Jafferi and Brian Gabrielli
Molecular Pharmacology September 1, 2010, 78 (3) 436-443; DOI: https://doi.org/10.1124/mol.110.065169
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