title: Enhanced efficacy of combined HDAC and PARP targeting in glioblastoma.
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.
authors.affiliation: Brain Tumor Biology Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100-DK, Copenhagen, Denmark.
authors.forename: Rikke D
authors.initials: RD
authors.lastname: Rasmussen
authors.affiliation: Brain Tumor Biology Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100-DK, Copenhagen, Denmark.
authors.forename: Madhavsai K
authors.initials: MK
authors.lastname: Gajjar
authors.affiliation: Brain Tumor Biology Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100-DK, Copenhagen, Denmark.
authors.forename: Kamilla E
authors.initials: KE
authors.lastname: Jensen
authors.affiliation: Brain Tumor Biology Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100-DK, Copenhagen, Denmark; Department of Radiation Biology, The Finsen Center, Copenhagen University Hospital, Blegdamsvej 9, 2100-DK, Copenhagen, Denmark. Electronic address: pkn@cancer.dk.
authors.forename: Petra
authors.initials: P
authors.lastname: Hamerlik
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D056284:Histone Deacetylase 1; C531550:olaparib
keywords: DNA repair; Genotoxic stress; Glioblastoma; Olaparib; SAHA