Enhanced efficacy of combined HDAC and PARP targeting in glioblastoma. Issue 5 (8th January 2016)

• Record Type: Journal Article
• Authors: Rasmussen, Rikke D.; Gajjar, Madhavsai K.; Jensen, Kamilla E.; Hamerlik, Petra
• Is Part Of: Molecular oncology. Volume 10:Issue 5(2016:May)
• Page Start: 751
• Page End: 763
• Publication Date: 2016-01-08
• Subjects: Glioblastoma -- Genotoxic stress -- DNA repair -- SAHA -- Olaparib; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1016/j.molonc.2015.12.014
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : Recent clinical trials have demonstrated that targeting chromatin remodeling factors is as a promising strategy for the treatment of glioblastoma (GBM). We and others have shown constitutive activation of DNA damage response (DDR) pathways in gliomas and suggested that targeting the DDR may improve the currently grim prognosis for patients. Based on our previous findings that inhibition of poly(ADP‐ribose) polymerase (PARP) increases radio‐sensitivity of the notoriously radio‐resistant GBM cells, we hypothesized that epigenetic down‐regulation of the DDR responses and induction of oxidative stress via HDAC inhibition would contribute to more efficient targeting of this deadly disease. Our data show that SAHA, an HDAC class I + II inhibitor, in combination with olaparib (PARP inhibitor): i) enhanced inhibition of GBM cell survival, ii) induced apoptosis, and iii) impaired cell cycle progression. These results provide a pre‐clinical rationale for combined administration of SAHA and olaparib, which are already individually in clinical trials. Highlights: PARP1 and HDAC1 are overexpressed in GBM. SAHA treatment down‐regulates the expression of key DNA repair proteins. SAHA treatment induces ROS, oxidative DNA lesions, PARylation and nuclear PARP1 translocation. Combined administration of SAHA and olaparib is more efficient at eradicating GBM cells than either drug alone.