Experimental treatment of pancreatic cancer with two novel histone deacetylase inhibitors |
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Authors: | Haefner Martin Bluethner Thilo Niederhagen Manuel Moebius Christian Wittekind Christian Mossner Joachim Caca Karel Wiedmann Marcus |
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Affiliation: | 1. Department of lntemal Medicine II, University of Leipzig, Philipp-Rosenthal-Str.27, Leipzig 04103, Germany 2. Institute of Pathology, University of Leipzig, Liebigstr.26, Leipzig 04103, Germany 3. Department of Surgery II, University of Leipzig, Liebigstrasse 20a, Leipzig 04103, Germany 4. Department of Internal Medicine I, Klinikurn Ludwigsburg, Posilipostr. 4, Ludwigsburg 71640, Germany |
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Abstract: | 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 v/tro in 8 human pancreatic cancer cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (M-I-r) 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. |
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Keywords: | Histone deacetylase inhibitor Pancreatic cancer NVP-LAQ824 NVP-LBH589 |
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