PT  - JOURNAL ARTICLE
AU  - Wood, Tabitha E.
AU  - Dalili, Shadi
AU  - Simpson, Craig D.
AU  - Sukhai, Mahadeo A.
AU  - Hurren, Rose
AU  - Anyiwe, Kika
AU  - Mao, Xinliang
AU  - Suarez Saiz, Fernando
AU  - Gronda, Marcela
AU  - Eberhard, Yanina
AU  - MacLean, Neil
AU  - Ketela, Troy
AU  - Reed, John C.
AU  - Moffat, Jason
AU  - Minden, Mark D.
AU  - Batey, Robert A.
AU  - Schimmer, Aaron D.
TI  - Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands
AID  - 10.1158/1535-7163.MCT-09-0495
DP  - 2010 Jan 01
TA  - Molecular Cancer Therapeutics
PG  - 246--256
VI  - 9
IP  - 1
4099  - http://mct.aacrjournals.org/content/9/1/246.short
4100  - http://mct.aacrjournals.org/content/9/1/246.full
SO  - Mol Cancer Ther2010 Jan 01; 9
AB  - Evasion of death receptor ligand–induced apoptosis represents an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli, decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands, we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore, we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby highlighting a new mechanism to overcome resistance to death receptor ligands. Mol Cancer Ther; 9(1); 246–56©2010 American Association for Cancer Research.