The histone deacetylase inhibitor valproic acid alters growth properties of renal cell carcinoma in vitro and in vivo.
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.
Jones
Jon
J
Department of Urology and Pediatric Urology, Goethe-University, Frankfurt am Main, Germany.
Juengel
Eva
E
Department of Urology and Pediatric Urology, Goethe-University, Frankfurt am Main, Germany.
Mickuckyte
Ausra
A
Department of Urology and Pediatric Urology, Goethe-University, Frankfurt am Main, Germany.
Hudak
Lukasz
L
Department of Urology and Pediatric Urology, Goethe-University, Frankfurt am Main, Germany.
Wedel
Steffen
S
Department of Urology and Pediatric Urology, Goethe-University, Frankfurt am Main, Germany.
Jonas
Dietger
D
Department of Urology and Pediatric Urology, Goethe-University, Frankfurt am Main, Germany.
Blaheta
Roman A
RA
Department of Urology and Pediatric Urology, Goethe-University, Frankfurt am Main, Germany.
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*
D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid