title: Inhibition of histone deacetylase 4 increases cytotoxicity of docetaxel in gastric cancer cells.
abstract: OBJECTIVE
  New treatment options for gastric cancer are in great demand. Histone deacetylases (HDACs) are exciting therapeutic targets, but only the class I HDACs 1, 2, and 3 have been studied in gastric cancer. We have investigated class IIa HDAC expression and inhibition in gastric cancer cells.
  
  
  METHODS
  We measured the level of 27 (phospho)proteins related to class IIa HDAC expression and function in ten laser-capture microdissection gastric tumor samples compared to patient-matched adjacent normal mucosa. Following, we evaluated class IIa HDAC inhibition by MC1568 in SNU-16 gastric cancer cells alone and in combination with cisplatin or docetaxel.
  
  
  RESULTS
  We demonstrate for the first time an increase of HDAC4 in gastric tumor cells. HDAC4 inhibition had a synergistic effect with docetaxel treatment, shifting the cellular response from a cytostatic to a cytotoxic phenotype. This effect was associated with increased levels of cleaved caspases 3 and 9 and increased acetylated histone H3 Lys9/Lys14.
  
  
  CONCLUSIONS
  These data support in vivo studies investigating the potential clinical use of HDAC4 inhibitors in combination with docetaxel for the treatment of gastric cancer, lowering treatment doses of docetaxel to reduce the burden of adverse side effects on patients.
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA; Fondazione IOM, Viagrande, Catania, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Colarossi
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Memeo
authors.forename: Cristina
authors.initials: C
authors.lastname: Colarossi
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aiello
authors.forename: Antonio
authors.initials: A
authors.lastname: Iuppa
authors.forename: Virginia
authors.initials: V
authors.lastname: Espina
authors.forename: Lance
authors.initials: L
authors.lastname: Liotta
authors.forename: Claudius
authors.initials: C
authors.lastname: Mueller
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000494:pharmacology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C577554:MC1568; D011758:Pyrroles; D012097:Repressor Proteins; D043823:Taxoids; D000077143:Docetaxel; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D002945:Cisplatin
keywords: Docetaxel; Gastric cancer; Histone deacetylation; Laser-capture microdissection; Reverse-phase protein microarrays