Basic Research
Copyright ©2007 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Sep 21, 2007; 13(35): 4761-4770
Published online Sep 21, 2007. doi: 10.3748/wjg.v13.i35.4761
Inhibition of histone deacetylase for the treatment of biliary tract cancer: A new effective pharmacological approach
Thilo Bluethner, Manuel Niederhagen, Karel Caca, Frederik Serr, Helmut Witzigmann, Christian Moebius, Joachim Mossner, Marcus Wiedmann
Thilo Bluethner, Joachim Mossner, Marcus Wiedmann, Department of Internal Medicine II, University of Leipzig, Philipp-Rosenthal-Str. 27, Leipzig 04103, Germany
Frederik Serr, Helmut Witzigmann, Christian Moebius, Department of Surgery II, University of Leipzig, Liebigstrasse 20a, 04103 Leipzig, Germany
Manuel Niederhagen, Institute of Pathology, University of Leipzig, Liebigstr. 26, Leipzig 04103, Germany
Karel Caca, Department of Internal Medicine I, Klinikum Ludwigsburg, Posilipostr. 4, Ludwigsburg 71640, Germany
Author contributions: All authors contributed equally to the work.
Supported by the Deutsche Krebshilfe, No. 10-2106-Wi 1
Correspondence to: Dr Marcus Wiedmann, Department of Internal Medicine II, University of Leipzig, Philipp-Rosenthal-Str. 27, 04103 Leipzig, Germany. wiedm@medizin.uni-leipzig.de
Telephone: +49-341-9712230 Fax: +49-341-9712239
Received: May 12, 2007
Revised: June 1, 2007
Accepted: June 4, 2007
Published online: September 21, 2007
Abstract

AIM: To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer.

METHODS: Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for acH4 and p21WAF-1/CIP-1, PARP assay, cell cycle analysis, TUNEL assay, and immunhistochemistry for MIB-1.

RESULTS: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines [mean IC50 (3 d) 0.11 and 0.05 μmol/L, respectively], and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21WAF-1/CIP-1, induction of apoptosis (PARP cleavage), and cell cycle arrest at G2/M checkpoint. After 28 d, NVP-LBH589 significantly reduced tumor mass by 66% (bile duct cancer) and 87% (gallbladder cancer) in vivo in comparison to placebo, and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis by TUNEL assay and reduced cell proliferation (MIB-1).

CONCLUSION: Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.

Keywords: Histone deacetylase inhibitor; Biliary tract cancer; Cholangiocarcinoma; NVP-LAQ824; NVP-LBH589