DNA damage response and anti-apoptotic proteins predict radiosensitization efficacy of HDAC inhibitors SAHA and LBH589 in patient-derived glioblastoma cells

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

doi:10.1016/j.canlet.2014.09.049

DNA damage response and anti-apoptotic proteins predict radiosensitization efficacy of HDAC inhibitors SAHA and LBH589 in patient-derived glioblastoma cells

Cancer Lett. 2015 Jan 28;356(2 Pt B):525-35. doi: 10.1016/j.canlet.2014.09.049. Epub 2014 Oct 8.

Affiliations

¹ Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
² Department of Genetics, Department Radiation Oncology, Cancer Genomics Netherlands, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
³ Department of Neurology/Neuro-oncology, Brain Tumor Center, Erasmus MC Cancer Institute, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
⁴ 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.

PMID: 25305451
DOI: 10.1016/j.canlet.2014.09.049

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.

Keywords: Bcl-XL; Chek2; Glioblastoma; HDAC inhibitors; Radiation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation / drug effects
Acetylation / radiation effects
Adult
Aged
Aged, 80 and over
Apoptosis / drug effects*
Apoptosis / radiation effects
Apoptosis Regulatory Proteins / metabolism*
Blotting, Western
Cell Proliferation / drug effects
Cell Proliferation / radiation effects
DNA Damage / drug effects
DNA Damage / genetics*
DNA Damage / radiation effects
Female
Glioblastoma / genetics
Glioblastoma / pathology
Glioblastoma / 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

Substances

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