title: Preclinical evaluation of dual PI3K-mTOR inhibitors and histone deacetylase inhibitors in head and neck squamous cell carcinoma.
abstract: BACKGROUND
  We examine the potential value of a series of clinically relevant PI3K-mTOR inhibitors alone, or in combination with histone deacetylase inhibitors, in a model of head and neck squamous cell carcinoma (HNSCC).
  
  
  METHODS
  Head and neck squamous cell carcinoma cell lines, human keratinocyte and HNSCC xenograft models were treated with histone deacetylase inhibitors (HDACIs) and new generation PI3K and dual PI3K-mTOR inhibitors either alone or in combination. Cell and tumour tissue viability and proliferation were then determined in vitro and in vivo.
  
  
  RESULTS
  Phosphatidylinositol-3-phosphate kinase, AKT and dual PI3K-mTOR inhibitors caused marked in vitro enhancement of cytotoxicity induced by HDACIs in HNSCC cancer cells. This effect correlates with AKT inhibition and is attenuated by expression of constitutively active AKT. Histone deacetylase inhibitor and phosphatidylinositol-3-phosphate kinase inhibitors (PI3KIs) inhibited tumour growth in xenograft models of HNSCC. Importantly, we observed intratumoural HDAC inhibition and PI3K inhibition as assessed by histone H3 acetylation status and phospho-AKT staining, respectively. However, we saw no evidence of improved efficacy with an HDACI/PI3KI combination.
  
  
  CONCLUSIONS
  That PI3K and dual PI3K-mTOR inhibitors possess antitumour effect against HNSCC in vivo.
authors: Department of Epithelial Pathobiology Group, Epithelial Cancer Programme, University of Queensland Diamantina Institute, Princess Alexandra Hospital, 4th Floor, Building 1, R wing, Ipswich Road, Woolloongabba, QLD 4102, Australia.
authors: R B
authors: RB
authors: Erlich
authors: Z
authors: Z
authors: Kherrouche
authors: D
authors: D
authors: Rickwood
authors: L
authors: L
authors: Endo-Munoz
authors: S
authors: S
authors: Cameron
authors: A
authors: A
authors: Dahler
authors: M
authors: M
authors: Hazar-Rethinam
authors: L M
authors: LM
authors: de Long
authors: K
authors: K
authors: Wooley
authors: A
authors: A
authors: Guminski
authors: N A
authors: NA
authors: Saunders
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D005260:Female; D006258:Head and Neck Neoplasms / Q000473:pathology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D007211:Indoles; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000077767:Panobinostat; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077337:Vorinostat; D000077767:Panobinostat; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases