PT  - JOURNAL ARTICLE
AU  - KeeMing Chia
AU  - Heather Beamish
AU  - Kaneez Jafferi
AU  - Brian Gabrielli
TI  - The histone deacetylase inhibitor MGCD0103 has both deacetylase and microtubule inhibitory activity
AID  - 10.1124/mol.110.065169
DP  - 2010 Jun 10
TA  - Molecular Pharmacology
PG  - mol.110.065169
4099  - http://molpharm.aspetjournals.org/content/early/2010/06/10/mol.110.065169.short
4100  - http://molpharm.aspetjournals.org/content/early/2010/06/10/mol.110.065169.full
AB  - Histone deacetylase inhibitors (HDACi) are currently being trialled or are in clinical use for treatment of a number of tumour 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 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 h and 12 h after treatment, and was cytotoxic 24 h post-treatment. These cell cycle effects were considerably distinct from the effects of suberic bishydroxamic acid (SBHA), 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. Similarly, it also specifically targeted tumor cells and was nontoxic to normal non-transformed cells. However, MGDC0103 also appeared to disrupt normal microtubule spindle formation whereas HDACi generally have only a minor effect on spindle formation. The effect of MGCD0103 on spindle formation was shown to be a consequence of microtubule destabilisation. This is the first example of a HDACi with microtubule destabilising activity and the combined effects of this drug has advantages for its therapeutic use.The American Society for Pharmacology and Experimental Therapeutics