Basic Research
Copyright ©2008 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Jun 21, 2008; 14(23): 3681-3692
Published online Jun 21, 2008. doi: 10.3748/wjg.14.3681
Experimental treatment of pancreatic cancer with two novel histone deacetylase inhibitors
Martin Haefner, Thilo Bluethner, Manuel Niederhagen, Christian Moebius, Christian Wittekind, Joachim Mossner, Karel Caca, Marcus Wiedmann
Martin Haefner, Thilo Bluethner, Joachim Mossner, Marcus Wiedmann, Department of Internal Medicine II, University of Leipzig, Philipp-Rosenthal-Str. 27, Leipzig 04103, Germany
Manuel Niederhagen, Christian Wittekind, Institute of Pathology, University of Leipzig, Liebigstr. 26, Leipzig 04103, Germany
Christian Moebius, Department of Surgery II, University of Leipzig, Liebigstrasse 20a, Leipzig 04103, Germany
Karel Caca, Department of Internal Medicine I, Klinikum Ludwigsburg, Posilipostr. 4, Ludwigsburg 71640, Germany
Author contributions: Wiedmann M and Caca K designed research; Haefner M, Bluethner T and Niederhagen M performed research; Wittekind C contributed analytic tools; Moebius C and Mossner J analyzed data and corrected the manuscript; and Wiedmann M wrote the paper.
Correspondence to: Dr. Marcus Wiedmann, Department of Internal Medicine II, University of Leipzig, Philipp-Rosenthal-Str. 27, Leipzig 04103, Germany.
Telephone: +49-341-9712230
Fax: +49-341-9712239
Received: January 25, 2008
Revised: May 4, 2008
Accepted: May 11, 2008
Published online: June 21, 2008

AIM: To investigate in vitro and in vivo treatment with histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 in pancreatic cancer.

METHODS: Cell-growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 8 human pancreatic cancer cell lines using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, the anti-tumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral activity of the drugs was assessed by immunoblotting for p21WAF-1, acH4, cell cycle analysis, TUNEL assay, and immunohistochemistry for MIB-1.

RESULTS: In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21WAF-1, cell cycle arrest at G2/M-checkpoint, and increased apoptosis. In vivo, NVP-LBH589 alone significantly reduced tumor mass and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed slightly increased apoptosis and no significant reduction of cell proliferation.

CONCLUSION: Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human pancreatic cancer, although the precise mechanism of in vivo drug action is not yet completely understood. Therefore, further preclinical and clinical studies for the treatment of pancreatic cancer are recommended.

Keywords: Histone deacetylase inhibitor, Pancreatic cancer, NVP-LAQ824, NVP-LBH589