title: Vorinostat in combination with bortezomib in patients with advanced malignancies directly alters transcription of target genes.
abstract: BACKGROUND
  Vorinostat is a small molecule inhibitor of class I and II histone deacetylase enzymes which alters the expression of target genes including the cell cycle gene p21, leading to cell cycle arrest and apoptosis.
  
  
  METHODS
  Patients enrolled in a phase I trial were treated with vorinostat alone on day 1 and vorinostat and bortezomib in combination on day 9. Paired biopsies were obtained in eleven subjects. Blood samples were obtained on days 1 and 9 of cycle 1 prior to dosing and 2 and 6 h post-dosing in all 60 subjects. Gene expression of p21, HSP70, AKT, Nur77, ERB1, and ERB2 was evaluated in peripheral blood mononuclear cells and tissue samples. Chromatin immunoprecipitation of p21, HSP70, and Nur77 was also performed in biopsy samples.
  
  
  RESULTS
  In peripheral blood mononuclear cells, Nur77 was significantly and consistently decreased 2 h after vorinostat administration on both days 1 and 9, median ratio of gene expression relative to baseline of 0.69 with interquartile range 0.49-1.04 (p < 0.001); 0.28 (0.15-0.7) (p < 0.001), respectively, with more pronounced decrease on day 9, when patients received both vorinostat and bortezomib. p21, a downstream target of Nur77, was significantly decreased on day 9, 2 and 6 h after administration of vorinostat and bortezomib, 0.67 (0.41-1.03) (p < 0.01); 0.44 (0.25-1.3) (p < 0.01), respectively. The ChIP assay demonstrated a protein-DNA interaction, in this case interaction of Nur77, HSP70 and p21 with acetylated histone H3, at baseline and at day 9 after treatment with vorinostat in tissue biopsies in most patients.
  
  
  CONCLUSIONS
  Vorinostat inhibits Nur77 expression, which in turn may decrease p21 and AKT expression in PBMCs. The influence of vorinostat on target gene expression in tumor tissue was variable; however, most patients demonstrated interaction of acetylated H3 with Nur77, HSP70, and p21 which provides evidence of interaction with the transcriptionally active acetylated H3.
authors.affiliation: University of Wisconsin Carbone Comprehensive Cancer Center, 600 Highland Avenue, Madison, WI 53792, USA. jmkolesar@pharmacy.wisc.edu
authors.forename: Jill M
authors.initials: JM
authors.lastname: Kolesar
authors.forename: Anne M
authors.initials: AM
authors.lastname: Traynor
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Holen
authors.forename: Tien
authors.initials: T
authors.lastname: Hoang
authors.forename: Songwon
authors.initials: S
authors.lastname: Seo
authors.forename: Kyungmann
authors.initials: K
authors.lastname: Kim
authors.forename: Dona
authors.initials: D
authors.lastname: Alberti
authors.forename: Igor
authors.initials: I
authors.lastname: Espinoza-Delgado
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: Howard H
authors.initials: HH
authors.lastname: Bailey
authors.forename: William R
authors.initials: WR
authors.lastname: Schelman
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001706:Biopsy; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011719:Pyrazines / Q000008:administration & dosage; D013997:Time Factors; D014158:Transcription, Genetic; D000077337:Vorinostat
chemical_list: D001897:Boronic Acids; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006877:Hydroxamic Acids; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011719:Pyrazines; D000077337:Vorinostat; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt
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