title: The histone deacetylase inhibitor valproic acid alters growth properties of renal cell carcinoma in vitro and in vivo.
abstract: Histone deacetylase (HDAC) inhibitors represent a promising class of antineoplastic agents which affect tumour growth, differentiation and invasion. The effects of the HDAC inhibitor valproic acid (VPA) were tested in vitro and in vivo on pre-clinical renal cell carcinoma (RCC) models. Caki-1, KTC-26 or A498 cells were treated with various concentrations of VPA during in vitro cell proliferation 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and to evaluate cell cycle manipulation. In vivo tumour growth was conducted in subcutaneous xenograft mouse models. The anti-tumoural potential of VPA combined with low-dosed interferon-alpha (IFN-alpha) was also investigated. VPA significantly and dose-dependently up-regulated histones H3 and H4 acetylation and caused growth arrest in RCC cells. VPA altered cell cycle regulating proteins, in particular CDK2, cyclin B, cyclin D3, p21 and Rb. In vivo, VPA significantly inhibited the growth of Caki-1 in subcutaneous xenografts, accompanied by a strong accumulation of p21 and bax in tissue specimens of VPA-treated animals. VPA-IFN-alpha combination markedly enhanced the effects of VPA monotherapy on RCC proliferation in vitro, but did not further enhance the anti-tumoural potential of VPA in vivo. VPA was found to have profound effects on RCC cell growth, lending support to the initiation of clinical testing of VPA for treating advanced RCC.
authors.affiliation: Department of Urology and Pediatric Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Jon
authors.initials: J
authors.lastname: Jones
authors.affiliation: Department of Urology and Pediatric Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Juengel
authors.affiliation: Department of Urology and Pediatric Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Ausra
authors.initials: A
authors.lastname: Mickuckyte
authors.affiliation: Department of Urology and Pediatric Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Hudak
authors.affiliation: Department of Urology and Pediatric Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Wedel
authors.affiliation: Department of Urology and Pediatric Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Dietger
authors.initials: D
authors.lastname: Jonas
authors.affiliation: Department of Urology and Pediatric Urology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Blaheta
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology*; D051379:Mice; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid