title: Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells.
abstract: Histone deacetylase inhibitors (HDIs) are a promising new class of antineoplastic agents with the ability to induce apoptosis and growth arrest of cancer cells. In addition, HDIs have been suggested to enhance the anticancer efficacy of other therapeutic regimens, such as ionizing radiation (IR) or chemotherapy. The objective of this study was to evaluate the activity of HDIs against medulloblastoma cells when applied either as single agents or in combination with IR, cytostatics, or TRAIL. The HDIs, suberoyl anilide hydroxamic acid (SAHA), sodium butyrate, and trichostatin A, were examined for their effects on the medulloblastoma cell lines, DAOY and UW228-2. We found that treatment with HDIs induced the dissipation of mitochondrial membrane potential, activation of caspase-9 and -3 and, consequently, apoptotic cell death. Moreover, all three HDIs significantly enhanced the cytotoxic effects of IR in DAOY cells. Likewise, treatment with SAHA markedly augmented the cytotoxicity of etoposide, while it had no effect on vincristine-mediated cell death. HDIs also potently increased the killing efficiency of TRAIL. TRAIL-induced, but not SAHA-induced, cell killing could be prevented by the caspase-8 inhibitor, z-IEDT-fmk. We conclude that HDIs may be useful for the treatment of medulloblastoma as monotherapy and particularly when given in combination with IR, appropriate cytostatics, or TRAIL.
authors.affiliation: Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst Moritz Arndt University, Greifswald, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Sonnemann
authors.forename: K Saravana
authors.initials: KS
authors.lastname: Kumar
authors.forename: Sandra
authors.initials: S
authors.lastname: Heesch
authors.forename: Cornelia
authors.initials: C
authors.lastname: Müller
authors.forename: Christoph
authors.initials: C
authors.lastname: Hartwig
authors.forename: Manfred
authors.initials: M
authors.lastname: Maass
authors.forename: Peter
authors.initials: P
authors.lastname: Bader
authors.forename: James F
authors.initials: JF
authors.lastname: Beck
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002087:Butyrates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D008562:Membrane Glycoproteins; D011838:Radiation-Sensitizing Agents; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C012589:trichostatin A; D000077337:Vorinostat; D014750:Vincristine; D005047:Etoposide; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases