Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2006-4-3
pubmed:abstractText
Hepatocellular carcinoma (HCC) displays a striking resistance to chemotherapeutic drugs or innovative tumor cell apoptosis-inducing agents such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Recently, we found 2 histone deacetylase inhibitors (HDAC-I), valproic acid and ITF2357, exhibiting inherent therapeutic activity against HCC. In TRAIL-sensitive cancer cells, the mechanism of HDAC-I-induced cell death has been identified to be TRAIL-dependent by inducing apoptosis in an autocrine fashion. In contrast, in HCC-derived cells, a prototype of TRAIL-resistant tumor cells, we found a HDAC-I-mediated apoptosis that works independently of TRAIL and upregulation of death receptors or their cognate ligands. Interestingly, TRAIL resistance could be overcome by a combinatorial application of HDAC-I and TRAIL, increasing the fraction of apoptotic cells two- to threefold compared with HDAC-I treatment alone, whereas any premature HDAC-I withdrawal rapidly restored TRAIL resistance. Furthermore, a tumor cell-specific downregulation of the FLICE inhibitory protein (FLIP) was observed, constituting a new mechanism of TRAIL sensitivity restoration by HDAC-I. In contrast, FLIP levels in primary human hepatocytes (PHH) from different donors were upregulated by HDAC-I. Importantly, combination HDAC-I/TRAIL treatment did not induce any cytotoxicity in nonmalignant PHH. In conclusion, HDAC-I compounds, exhibiting a favorable in vivo profile and inherent activity against HCC cells, are able to selectively overcome the resistance of HCC cells toward TRAIL. Specific upregulation of intracellular FLIP protein levels in nonmalignant hepatocytes could enhance the therapeutic window for clinical applications of TRAIL, opening up a highly specific new treatment option for advanced HCC.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, http://linkedlifedata.com/resource/pubmed/chemical/Apoptosis Regulatory Proteins, http://linkedlifedata.com/resource/pubmed/chemical/CASP8 and FADD-Like Apoptosis..., http://linkedlifedata.com/resource/pubmed/chemical/CFLAR protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/HDAC1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Histone Deacetylase 1, http://linkedlifedata.com/resource/pubmed/chemical/Histone Deacetylase Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Hydroxamic Acids, http://linkedlifedata.com/resource/pubmed/chemical/ITF 2357, http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides..., http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins, http://linkedlifedata.com/resource/pubmed/chemical/TNF-Related Apoptosis-Inducing..., http://linkedlifedata.com/resource/pubmed/chemical/TNFSF10 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha, http://linkedlifedata.com/resource/pubmed/chemical/Valproic Acid
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0270-9139
pubmed:author
pubmed:issnType
Print
pubmed:volume
43
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
425-34
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:16583461-Antineoplastic Agents, pubmed-meshheading:16583461-Apoptosis, pubmed-meshheading:16583461-Apoptosis Regulatory Proteins, pubmed-meshheading:16583461-CASP8 and FADD-Like Apoptosis Regulating Protein, pubmed-meshheading:16583461-Carcinoma, Hepatocellular, pubmed-meshheading:16583461-Cell Line, Tumor, pubmed-meshheading:16583461-Cells, Cultured, pubmed-meshheading:16583461-Drug Resistance, Neoplasm, pubmed-meshheading:16583461-Enzyme Inhibitors, pubmed-meshheading:16583461-Hepatocytes, pubmed-meshheading:16583461-Histone Deacetylase 1, pubmed-meshheading:16583461-Histone Deacetylase Inhibitors, pubmed-meshheading:16583461-Humans, pubmed-meshheading:16583461-Hydroxamic Acids, pubmed-meshheading:16583461-Intracellular Signaling Peptides and Proteins, pubmed-meshheading:16583461-Liver Neoplasms, pubmed-meshheading:16583461-Membrane Glycoproteins, pubmed-meshheading:16583461-Oligonucleotide Array Sequence Analysis, pubmed-meshheading:16583461-TNF-Related Apoptosis-Inducing Ligand, pubmed-meshheading:16583461-Tumor Necrosis Factor-alpha, pubmed-meshheading:16583461-Up-Regulation, pubmed-meshheading:16583461-Valproic Acid
pubmed:year
2006
pubmed:articleTitle
HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL.
pubmed:affiliation
Department of Internal Medicine I, Medical University Clinic, Tübingen, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't