Article type: Research Article
Authors: Di Fazio, Pietro; ; ; | Schneider-Stock, Regine; | Neureiter, Daniel | Okamoto, Kinya; | Wissniowski, Till | Gahr, Susanne | Quint, Karl; | Meissnitzer, Matthias | Alinger, Beate | Montalbano, Roberta; | Sass, Gabriele | Hohenstein, Bernd | Hahn, Eckhart G. | Ocker, Matthias; ;
Affiliations: Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany | Dipartimento di Scienze Biochimiche, Universita di Palermo, Policlinico, Palermo, Italy | Department of Pathology, University Hospital Erlangen, Erlangen, Germany | Institute of Pathology, Salzburger Landeskliniken, Paracelsus Private Medical University, Salzburg, Austria | Second Department of Internal Medicine, Tottori University School of Medicine, Tottori, Japan | Division of Experimental Immunology and Hepatology, University Medical Center Hamburg Eppendorf, Hamburg, Germany | Department of Medicine 4, University Hospital Erlangen, Erlangen, Germany | Institute for Surgical Research, Philipps-University Marburg, Marburg, Germany
Note: [] The first two authors contributed equally to this work.
Note: [] Corresponding author: Prof. Dr. Matthias Ocker, MD, Institute for Surgical Research, Baldingerstrasse, 35043 Marburg, Germany. Tel.: +49 6421 5868930; Fax: +49 6421 5868926; E-mail: [email protected].
Abstract: Inhibition of deacetylases represents a new treatment option for human cancer diseases. We applied the novel and potent pan-deacetylase inhibitor panobinostat (LBH589) to human hepatocellular carcinoma models and investigated by which pathways tumor cell survival is influenced. HepG2 (p53wt) and Hep3B (p53null) responded to panobinostat treatment with a reduction of cell proliferation and a significant increase in apoptotic cell death at low micromolar concentrations. Apoptosis was neither mediated by the extrinsic nor the intrinsic pathway but quantitative RT-PCR showed an upregulation of CHOP, a marker of the unfolded protein response and endoplasmic reticulum stress with subsequent activation of caspase 12. Dependent on the p53 status, a transcriptional upregulation of p21cip1/waf1, an increased phosphorylation of H2AX, and an activation of the MAPK pathway were observed. In a subcutaneous xenograft model, daily i.p. injections of 10 mg/kg panobinostat lead to a significant growth delay with prolonged overall survival, mediated by reduced tumor cell proliferation, increased apoptosis and reduced angiogenesis in tumor xenografts. Panobinostat increased the acetylation of histones H3 and H4. Panobinostat is a well tolerated new treatment option for HCC that activates alternative pathways of apoptosis, also in p53-deficient tumors.
Keywords: p21^cip1/waf1, unfolded protein response (UPR), endoplasmic reticulum stress, caspase 12, transcriptional regulation, xenograft model, HDAC, LBH589
DOI: 10.3233/CLO-2010-0511
Journal: Analytical Cellular Pathology, vol. 32, no. 4, pp. 285-300, 2010
