New histone deacetylase inhibitors as potential therapeutic tools for advanced prostate carcinoma

  • The anti-epileptic drug valproic acid is also under trial as an anti-cancer agent due to its histone deacetylase (HDAC) inhibitory properties. However, the effects of valproic acid (VPA) are limited and concentrations required for exerting anti-neoplastic effects in vitro may not be reached in tumour patients. In this study, we tested in vitro and in vivo effects of two VPA-derivatives (ACS2, ACS33) on pre-clinical prostate cancer models. PC3 and DU-145 prostate tumour cell lines were treated with various concentrations of ACS2 or ACS33 to perform in vitro cell proliferation 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and to evaluate tumour cell adhesion to endothelial cell monolayers. Analysis of acetylated histones H3 and H4 protein expression was performed by western blotting. In vivo tumour growth was conducted in subcutaneous xenograft mouse models. Tumour sections were assessed by immunohistochemistry for histone H3 acetylation and proliferation. ACS2 and ACS33 significantly up-regulated histone H3 and H4 acetylation in prostate cancer cell lines. In micromolar concentrations both compounds exerted growth arrest in PC3 and DU-145 cells and prevented tumour cell attachment to endothelium. In vivo, ACS33 inhibited the growth of PC3 in subcutaneous xenografts. Immunohistochemistry and western blotting confirmed increased histone H3 acetylation and reduced proliferation. ACS2 and ACS33 represent novel VPA derivatives with superior anti-tumoural activities, compared to the mother compound. This investigation lends support to the clinical testing of ACS2 or ACS33 for the treatment of prostate cancer.

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Author:Steffen Alexander WedelGND, Anna Sparatore, Piero Del Soldato, Salah-Eddin al- BatranORCiDGND, Akin Atmaca, Eva JüngelORCiDGND, Lukasz HudakGND, Dietger JonasGND, Roman A. BlahetaORCiD
Pubmed Id:
Parent Title (English):Journal of cellular and molecular medicine
Place of publication:Hoboken, NJ
Document Type:Article
Date of Publication (online):2008/02/08
Date of first Publication:2008/02/08
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2013/02/08
Tag:HDAC; VPA-analogues; adhesion; proliferation; prostate cancer; valproic acid
Page Number:10
First Page:2457
Last Page:2466
© 2008 The Authors Journal compilation © 2008 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. This is an Open Access article under the terms of the Creative Commons Attribution Non Commercial License which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell 3.0