The pan-deacetylase inhibitor panobinostat inhibits growth of hepatocellular carcinoma models by alternative pathways of apoptosis

• Published in: Cellular oncology : the official journal of the International Society for Cellular Oncology 2010-01, Vol.32 (4), p.285-300
• Main 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
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Proliferation - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Hep G2 Cells; Histone Deacetylase Inhibitors - pharmacology; Histones - metabolism; Humans; Hydroxamic Acids - pharmacology; Indoles; Male; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Other; Panobinostat; Transcription Factor CHOP - biosynthesis; Transcription Factor CHOP - genetics; Tumor Burden - drug effects; Tumor Suppressor Protein p53 - deficiency; Unfolded Protein Response - drug effects
• ISSN: 1570-5870; 1875-8606
• DOI: 10.3233/CLO-2010-0511

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 p21(cip1/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.