Source:http://linkedlifedata.com/resource/pubmed/id/18256683
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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
5
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pubmed:dateCreated |
2008-5-14
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pubmed:abstractText |
We have developed a potent, histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 with >200-fold selectivity over the other HDAC isoforms. PCI-34051 induces caspase-dependent apoptosis in cell lines derived from T-cell lymphomas or leukemias, but not in other hematopoietic or solid tumor lines. Unlike broad-spectrum HDAC inhibitors, PCI-34051 does not cause detectable histone or tubulin acetylation. Cells defective in T-cell receptor signaling were still sensitive to PCI-34051-induced apoptosis, whereas a phospholipase C-gamma1 (PLCgamma1)-defective line was resistant. Jurkat cells showed a dose-dependent decrease in PCI-34051-induced apoptosis upon treatment with a PLC inhibitor U73122, but not with an inactive analog. We found that rapid intracellular calcium mobilization from endoplasmic reticulum (ER) and later cytochrome c release from mitochondria are essential for the apoptotic mechanism. The rapid Ca(2+) flux was dependent on PCI-34051 concentration, and was blocked by the PLC inhibitor U73122. Further, apoptosis was blocked by Ca(2+) chelators (BAPTA) and enhanced by Ca(2+) effectors (thapsigargin), supporting this model. These studies show that HDAC8-selective inhibitors have a unique mechanism of action involving PLCgamma1 activation and calcium-induced apoptosis, and could offer benefits including a greater therapeutic index for treating T-cell malignancies.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Calcium,
http://linkedlifedata.com/resource/pubmed/chemical/HDAC8 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Histone Deacetylase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Histone Deacetylases,
http://linkedlifedata.com/resource/pubmed/chemical/Indoles,
http://linkedlifedata.com/resource/pubmed/chemical/Phospholipase C gamma,
http://linkedlifedata.com/resource/pubmed/chemical/Repressor Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
1476-5551
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pubmed:author | |
pubmed:issnType |
Electronic
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pubmed:volume |
22
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1026-34
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:18256683-Apoptosis,
pubmed-meshheading:18256683-Calcium,
pubmed-meshheading:18256683-Cell Line, Tumor,
pubmed-meshheading:18256683-Histone Deacetylase Inhibitors,
pubmed-meshheading:18256683-Histone Deacetylases,
pubmed-meshheading:18256683-Humans,
pubmed-meshheading:18256683-Indoles,
pubmed-meshheading:18256683-Lymphoma, T-Cell,
pubmed-meshheading:18256683-Phospholipase C gamma,
pubmed-meshheading:18256683-Repressor Proteins
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pubmed:year |
2008
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pubmed:articleTitle |
A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas.
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pubmed:affiliation |
Department of Cancer Biology, Pharmacyclics Inc., Sunnyvale, CA 94085, USA. sriram@pcyc.com
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pubmed:publicationType |
Journal Article
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