title: Mechanism of growth inhibition of prostate cancer xenografts by valproic acid.
abstract: Valproic Acid (VPA), a histone deacetylase inhibitor, has been demonstrated to cause a marked decrease in proliferation of prostate cancer (PCa) cells in vitro and a significant reduction in tumor volume in vivo. The goal of this study is to better understand the VPA-induced growth inhibition in vivo, by studying expression of various markers in PCa xenografts.
  
  
  METHODS
  For in vitro experiments, PCa cells were treated with 0, 0.6, and 1.2 mM VPA for 14 days. For in vivo models, experimental animals received 0.4% VPA in drinking water for 35 days. Tissue microarray was generated using cell pellets and excised xenografts.
  
  
  RESULTS
  VPA treatment causes cell cycle arrest in PCa cells in vivo, as determined by increase in p21 and p27 and decrease in cyclin D1 expression. Increased expression of cytokeratin18 was also seen in xenografts. LNCaP xenografts in treated animals had reduced androgen receptor (AR) expression. While decreased proliferation was found in vitro, increase in apoptosis was found to be the reason for decreased tumor growth in vivo. Also, an anti-angiogenic effect was observed after VPA treatment.
  
  
  CONCLUSIONS
  VPA inhibits tumor growth by multiple mechanisms including cell cycle arrest, induction of differentiation, and inhibition of growth of tumor vasculature.
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Marburg 205A, 600 North Wolfe Street, Baltimore, MD 21287, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Sidana
authors.forename: Muwen
authors.initials: M
authors.lastname: Wang
authors.forename: Shabana
authors.initials: S
authors.lastname: Shabbeer
authors.forename: Wasim H
authors.initials: WH
authors.lastname: Chowdhury
authors.forename: George
authors.initials: G
authors.lastname: Netto
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Lupold
authors.forename: Michael
authors.initials: M
authors.lastname: Carducci
authors.forename: Ronald
authors.initials: R
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000503:physiopathology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D014635:Valproic Acid / Q000008:administration & dosage*
chemical_list: D056572:Histone Deacetylase Inhibitors; D009363:Neoplasm Proteins; D014635:Valproic Acid