title: 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 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.
authors.affiliation: Department of Medicine 1, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Pietro
authors.initials: P
authors.lastname: Di Fazio
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.forename: Kinya
authors.initials: K
authors.lastname: Okamoto
authors.forename: Till
authors.initials: T
authors.lastname: Wissniowski
authors.forename: Susanne
authors.initials: S
authors.lastname: Gahr
authors.forename: Karl
authors.initials: K
authors.lastname: Quint
authors.forename: Matthias
authors.initials: M
authors.lastname: Meissnitzer
authors.forename: Beate
authors.initials: B
authors.lastname: Alinger
authors.forename: Roberta
authors.initials: R
authors.lastname: Montalbano
authors.forename: Gabriele
authors.initials: G
authors.lastname: Sass
authors.forename: Bernd
authors.initials: B
authors.lastname: Hohenstein
authors.forename: Eckhart G
authors.initials: EG
authors.lastname: Hahn
authors.forename: Matthias
authors.initials: M
authors.lastname: Ocker
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D000077767:Panobinostat; D051742:Transcription Factor CHOP / Q000096:biosynthesis* / Q000235:genetics; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497249:DDIT3 protein, human; C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D016159:Tumor Suppressor Protein p53; D051742:Transcription Factor CHOP; D000077767:Panobinostat