title: Histone deacetylase inhibitors as potential therapeutic approaches for chordoma: an immunohistochemical and functional analysis.
abstract: Chordomas are rare malignancies of the axial skeleton. Therapy is mainly restricted to surgery. This study investigates histone deacetylase (HDAC) inhibitors as potential therapeutics for chordomas. Immunohistochemistry (IHC) was performed using the HDAC 1-6 antibodies on 50 chordoma samples (34 primary tumors, 16 recurrences) from 44 patients (27 male, 17 female). Pan-HDAC-inhibitors Vorinostat (SAHA), Panobinostat (LBH-589), and Belinostat (PXD101) were tested for their efficacy in the chordoma cell line MUG-Chor1 via Western blot, cell cycle analysis, caspase 3/7 activity (MUG-Chor1, UCh-1), cleaved caspase-3, and PARP cleavage. p-Values below 0.05 were considered significant. IHC was negative for HDAC1, positive for HDAC2 in most (n = 36; 72%), and for HDACs 3-6 in all specimens available (n = 43; 86%). HDAC6 expression was strongest. SAHA and LBH-589, but not PXD101 caused a significant increase of G2/M phase cells and of cleaved caspase-3 (p = 0.0003, and p = 0.0014 after 72 h, respectively), and a peak of caspase 3/7 activity. PARP cleavage confirmed apoptosis. The presented chordoma series expressed HDACs 2-6 with strongest expression of HDAC6. SAHA and LBH-589 significantly increased apoptosis and changed cell cycle distribution in vitro. HDAC-inhibitors should be further evaluated as therapeutic options for chordoma.
authors.affiliation: Department of Orthopaedics and Orthopaedic Surgery, Medical University of Graz, Auenbruggerplatz 5, 8036, Graz, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Scheipl
authors.forename: Birgit
authors.initials: B
authors.lastname: Lohberger
authors.forename: Beate
authors.initials: B
authors.lastname: Rinner
authors.forename: Elke Verena
authors.initials: EV
authors.lastname: Froehlich
authors.forename: Alfred
authors.initials: A
authors.lastname: Beham
authors.forename: Franz
authors.initials: F
authors.lastname: Quehenberger
authors.forename: Aron
authors.initials: A
authors.lastname: Lazáry
authors.forename: Peter
authors.initials: P
authors.lastname: Pal Varga
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.forename: Andreas
authors.initials: A
authors.lastname: Leithner
authors.forename: Bernadette
authors.initials: B
authors.lastname: Liegl
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002817:Chordoma / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000032:analysis; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D000077767:Panobinostat; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077337:Vorinostat; D000077767:Panobinostat; D053148:Caspase 3; D006655:Histone Deacetylases
keywords: HDAC; HDAC inhibitors; chordoma; survival; targeted therapies