title: DNA damage response and anti-apoptotic proteins predict radiosensitization efficacy of HDAC inhibitors SAHA and LBH589 in patient-derived glioblastoma cells.
abstract: HDAC inhibitors have radiosensitizing effects in established cancer cell lines. This study was conducted to compare the efficacy of SAHA, LBH589, Valproic Acid (VPA), MS275 and Scriptaid in the patient-derived glioblastoma model. In more detail, SAHA and LBH589 were evaluated to determine predictors of response. Acetylated-histone-H3, γH2AX/53BP1, (p)Chek2/ATM, Bcl-2/Bcl-XL, p21(CIP1/WAF1) and caspase-3/7 were studied in relation to response. SAHA sensitized 50% of cultures, LBH589 45%, VPA and Scriptaid 40% and MS275 60%. Differences after treatment with SAHA/RTx or LBH589/RTx in a sensitive and resistant culture were increased acetylated-H3, caspase-3/7 and prolonged DNA damage repair γH2AX/53BP1 foci. pChek2 was found to be associated with both SAHA/RTx and LBH589/RTx response with a positive predictive value (PPV) of 90%. Bcl-XL had a PPV of 100% for LBH589/RTx response. Incubation with HDACi 24 and 48 hours pre-RTx resulted in the best efficacy of combination treatment. In conclusion a subset of patient-derived glioblastoma cultures were sensitive to HDACi/RTx. For SAHA and LBH589 responses were strongly associated with pChek2 and Bcl-XL, which warrant further clinical exploration. Additional information on responsiveness was obtained by DNA damage response markers and apoptosis related proteins.
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Lotte M E Berghauser
authors.initials: LM
authors.lastname: Pont
authors.affiliation: Department of Genetics, Department Radiation Oncology, Cancer Genomics Netherlands, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Kishan
authors.initials: K
authors.lastname: Naipal
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Jenneke J
authors.initials: JJ
authors.lastname: Kloezeman
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Venkatesan
authors.affiliation: Department of Neurology/Neuro-oncology, Brain Tumor Center, Erasmus MC Cancer Institute, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: van den Bent
authors.affiliation: Department of Genetics, Department Radiation Oncology, Cancer Genomics Netherlands, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Dik C
authors.initials: DC
authors.lastname: van Gent
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Clemens M F
authors.initials: CM
authors.lastname: Dirven
authors.affiliation: Department of Genetics, Department Radiation Oncology, Cancer Genomics Netherlands, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Roland
authors.initials: R
authors.lastname: Kanaar
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Martine L M
authors.initials: ML
authors.lastname: Lamfers
authors.affiliation: Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands; Department of Neurosurgery, Elizabeth Medical Hospital, Tilburg, The Netherlands. Electronic address: s.leenstra@erasmusmc.nl.
authors.forename: Sieger
authors.initials: S
authors.lastname: Leenstra
mesh_terms: D000107:Acetylation / Q000187:drug effects / Q000528:radiation effects; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D000077767:Panobinostat; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000077337:Vorinostat
chemical_list: D051017:Apoptosis Regulatory Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D011838:Radiation-Sensitizing Agents; D000077337:Vorinostat; D000077767:Panobinostat
keywords: Bcl-XL; Chek2; Glioblastoma; HDAC inhibitors; Radiation