title: The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells.
abstract: BACKGROUND
  Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches.
  
  
  METHODS
  Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines.
  
  
  RESULTS
  HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy.
  
  
  CONCLUSIONS
  Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors.
authors.affiliation: Department of Pediatric Hematology and Oncology, University Childrens' Hospital Muenster, Muenster, Germany.
authors.forename: Kornelius
authors.initials: K
authors.lastname: Kerl
authors.forename: David
authors.initials: D
authors.lastname: Ries
authors.forename: Rebecca
authors.initials: R
authors.lastname: Unland
authors.forename: Christiane
authors.initials: C
authors.lastname: Borchert
authors.forename: Natalia
authors.initials: N
authors.lastname: Moreno
authors.forename: Martin
authors.initials: M
authors.lastname: Hasselblatt
authors.forename: Heribert
authors.initials: H
authors.lastname: Jürgens
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Dennis
authors.initials: D
authors.lastname: Görlich
authors.forename: Maria
authors.initials: M
authors.lastname: Eveslage
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.forename: Michael
authors.initials: M
authors.lastname: Meisterernst
authors.forename: Michael
authors.initials: M
authors.lastname: Frühwald
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D017313:Fenretinide / Q000008:administration & dosage; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D018335:Rhabdoid Tumor / Q000378:metabolism* / Q000473:pathology; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D017313:Fenretinide; D000077337:Vorinostat; D004317:Doxorubicin; D006655:Histone Deacetylases