title: Pan-histone deacetylase inhibitor panobinostat sensitizes gastric cancer cells to anthracyclines via induction of CITED2.
abstract: OBJECTIVE
  Chemotherapy modestly prolongs survival of patients with advanced gastric cancer, but strategies are needed to increase its efficacy. Histone deacetylase (HDAC) inhibitors modify chromatin and can block cancer cell proliferation and promote apoptosis.
  
  
  METHODS
  Gastric cancer cell lines were incubated with the HDAC inhibitor LBH589 (Panobinostat, Novartis, Germany); levels of proliferation, apoptosis, histone acetylation, and gene expression were determined. We identified factors downstream of HDAC that regulated chemoresistance. The effects of combination chemotherapy of HDAC inhibitors and anthracyclines were studied in CEA424/SV40 T-antigen (CEA/Tag) transgenic mice, which develop gastric tumors. We analyzed gastric tumor samples from patients using immunohistochemistry.
  
  
  RESULTS
  HDAC2 was expressed in human gastric cancer cell lines and tumor samples, as well as in gastric tumors from CEA/Tag mice, compared with non-neoplastic gastric tissue. LBH589 inhibited proliferation of cancer cells in vitro. LBH589 down-regulated expression of genes that mediate anthracycline resistance by activating expression of Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), a gene that mediates sensitivity to chemotherapeutics. Pre-incubation of cells with an HDAC inhibitor and overexpression of CITED2-sensitized gastric cell lines to anthracycline-mediated cell death. In CEA/Tag mice, LBH589 induced tumor-cell expression of CITED2 and increased the efficacy of anthracycline to reduce tumor growth. Levels of CITED2 were increased in gastric tumor samples from patients who had complete responses to epirubicin.
  
  
  CONCLUSIONS
  The HDAC inhibitor LBH589 can overcome the resistance of mouse gastric cancer cells to anthracyclines by inducing expression of CITED2. Levels of CITED2 in gastric tumors correlate with patients' response to epirubicin. LBH589 might be used to increase the response of patients to anthracyclines.
authors.affiliation: Department of Medicine II, Universität München, München, Germany.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Regel
authors.forename: Lisa
authors.initials: L
authors.lastname: Merkl
authors.forename: Teresa
authors.initials: T
authors.lastname: Friedrich
authors.forename: Elke
authors.initials: E
authors.lastname: Burgermeister
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Zimmermann
authors.forename: Henrik
authors.initials: H
authors.lastname: Einwächter
authors.forename: Ken
authors.initials: K
authors.lastname: Herrmann
authors.forename: Rupert
authors.initials: R
authors.lastname: Langer
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.forename: Ralf
authors.initials: R
authors.lastname: Hofheinz
authors.forename: Roland
authors.initials: R
authors.lastname: Schmid
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Ebert
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015251:Epirubicin / Q000494:pharmacology; D015870:Gene Expression; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles; D051379:Mice; D008822:Mice, Transgenic; D000077767:Panobinostat; D012097:Repressor Proteins / Q000235:genetics*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; C486381:CITED2 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D012097:Repressor Proteins; D015534:Trans-Activators; D015251:Epirubicin; D000077767:Panobinostat