title: Valproic acid and interferon-alpha synergistically inhibit neuroblastoma cell growth in vitro and in vivo.
abstract: Valproic acid (VPA) as a differentiation inducing anti-neoplastic substance is currently tested in solid tumour and leukaemia patients. Previously, we were able to show that the anti-cancer activity of VPA was synergistically increased by interferon-alpha (IFN-alpha) in Be(2)-C neuroblastoma (NB) cells. Now, we studied the effects of VPA in combination with IFN-alpha on two other NB cell lines. UKF-NB-2 and UKF-NB-3 cell growth was synergistically inhibited by VPA and IFN-alpha. Cell cycle investigations revealed massive accumulation of cells in G0/G1-phase after a combined treatment with VPA and IFN-alpha. The VPA-induced accumulation of acetylated histones in NB cell nuclei that indicates inhibition of histone deacetylases was not further enhanced by the combination treatment with IFN-alpha. Most strikingly, VPA plus IFN-alpha synergistically inhibited growth of UKF-NB-3 xenograft tumours in nude mice and induced complete cures in two out of six animals, while single treatment merely inhibited tumour growth. The results of this study together with our previous report strongly encourage the clinical evaluation of VPA and IFN-alpha for NB patients.
authors.affiliation: Institut für Medizinische Virologie, Klinikum der J.W. Goethe Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.forename: Tatyana
authors.initials: T
authors.lastname: Suhan
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Cinatl
authors.forename: Pablo Hernáiz
authors.initials: PH
authors.lastname: Driever
authors.forename: Jindrich
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D000818:Animals; D002467:Cell Nucleus; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D016898:Interferon-alpha / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000473:pathology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D014635:Valproic Acid