Analytical Cellular Pathology

Analytical Cellular Pathology / 2010 / Article

Open Access

Volume 32 |Article ID 847218 | https://doi.org/10.3233/CLO-2010-0511

Pietro Di Fazio, Regine Schneider-Stock, Daniel Neureiter, Kinya Okamoto, Till Wissniowski, Susanne Gahr, Karl Quint, Matthias Meissnitzer, Beate Alinger, Roberta Montalbano, Gabriele Sass, Bernd Hohenstein, Eckhart G. Hahn, Matthias Ocker, "The Pan-Deacetylase Inhibitor Panobinostat Inhibits Growth of Hepatocellular Carcinoma Models by Alternative Pathways of Apoptosis", Analytical Cellular Pathology, vol. 32, Article ID 847218, 16 pages, 2010. https://doi.org/10.3233/CLO-2010-0511

The Pan-Deacetylase Inhibitor Panobinostat Inhibits Growth of Hepatocellular Carcinoma Models by Alternative Pathways of Apoptosis

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.

Copyright © 2010 Hindawi Publishing Corporation and the authors. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

 PDF Download Citation Citation
 Order printed copiesOrder
Views253
Downloads411
Citations