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: Lotte M E Berghauser Pont, Kishan Naipal, Jenneke J Kloezeman, Subramanian Venkatesan, Martin van den Bent, Dik C van Gent, Clemens M F Dirven, Roland Kanaar, Martine L M Lamfers, Sieger Leenstra
• Journal: Cancer letters (Cancer Lett) Vol. 356 Issue 2 Pt B Pg. 525-35 (Jan 28 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25305451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Indoles
• Radiation-Sensitizing Agents
• Vorinostat
• Panobinostat

Topics

• Acetylation (drug effects, radiation effects)
• Adult
• Aged
• Aged, 80 and over
• Apoptosis (drug effects, radiation effects)
• Apoptosis Regulatory Proteins (metabolism)
• Blotting, Western
• Cell Proliferation (drug effects, radiation effects)
• DNA Damage (drug effects, genetics, radiation effects)
• Female
• Glioblastoma (genetics, pathology, therapy)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hydroxamic Acids (pharmacology)
• Immunoenzyme Techniques
• Indoles (pharmacology)
• Male
• Middle Aged
• Panobinostat
• Radiation-Sensitizing Agents (pharmacology)
• Tumor Cells, Cultured
• Vorinostat