Open AccessThe histone deacetylase inhibitor valproic acid alters growth properties of renal cell carcinoma in vitro and in vivo
Author(s) -
Jones Jon,
Juengel Eva,
Mickuckyte Ausra,
Hudak Lukasz,
Wedel Steffen,
Jonas Dietger,
Blaheta Roman A.
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2008.00436.x
Subject(s) - in vivo , cell growth , histone deacetylase , valproic acid , cancer research , growth inhibition , cell cycle , pharmacology , in vitro , histone deacetylase inhibitor , chemistry , acetylation , cyclin b1 , cell , biology , histone , biochemistry , cyclin dependent kinase 1 , epilepsy , microbiology and biotechnology , neuroscience , gene
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‐α (IFN‐α) 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‐α 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.