Vorinostat in combination with bortezomib in patients with advanced malignancies directly alters transcription of target genes

Cancer Chemother Pharmacol. 2013 Sep;72(3):661-7. doi: 10.1007/s00280-013-2242-6. Epub 2013 Aug 1.

Abstract

Introduction: 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.

Conclusion: 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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biopsy
  • Boronic Acids / administration & dosage
  • Bortezomib
  • Chromatin Immunoprecipitation
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Hydroxamic Acids / administration & dosage
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Proto-Oncogene Proteins c-akt / genetics
  • Pyrazines / administration & dosage
  • Time Factors
  • Transcription, Genetic
  • Vorinostat

Substances

  • Boronic Acids
  • Cyclin-Dependent Kinase Inhibitor p21
  • Hydroxamic Acids
  • NR4A1 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Pyrazines
  • Vorinostat
  • Bortezomib
  • Proto-Oncogene Proteins c-akt