title: PARP-1 inhibitors DPQ and PJ-34 negatively modulate proinflammatory commitment of human glioblastoma cells.
abstract: Poly(ADP-ribose) polymerases (PARPs) are recognized as key regulators of cell survival or death. PARP-1 is essential to the repair of DNA single-strand breaks via the base excision repair pathway. The enzyme may be overactivated in response to inflammatory cues, thus depleting cellular energy pools and eventually causing cell death. Accordingly, PARP-1 inhibitors, acting by competing with its physiological substrate NAD(+), have been proposed to play a protective role in a wide range of inflammatory and ischemia/reperfusion-associated diseases. Recently, it has also been reported that PARP-1 regulates proinflammatory mediators, including cytokines, chemokines, adhesion molecules, and enzymes (e.g., iNOS). Furthermore, PARP-1 has been shown to act as a coactivator of NF-κB- and other transcription factors implicated in stress/inflammation, as AP-1, Oct-1, SP-1, HIF, and Stat-1. To further substantiate this hypothesis, we tested the biomolecular effects of PARP-1 inhibitors DPQ and PJ-34 on human glioblastoma cells, induced to a proinflammatory state with lipopolysaccharide and Interferon-γ. PARP-1 expression was evaluated by laser scanning confocal microscopy immunofluorescence (LSM); nitrite production, LDH release and cell viability were also determined. LSM of A-172, SNB-19 and CAS-1 cells demonstrated that DPQ and PJ-34 downregulate PARP-1 expression; they also cause a decrease of LDH release and nitrite production, while increasing cell viability. Similar effects were caused in all three cell lines by N-mono-methyl-arginine, a well known iNOS inhibitor, and by L-carnosine and trehalose, two antioxidant molecules. These results demonstrate that, similar to other well characterized drugs, DPQ and PJ-34 reduce cell inflammation and damage that follow PARP-1 overexpression, while they increase cell survival: this suggests their potential exploitation in clinical Medicine.
authors.affiliation: Dipartimento Gian Filippo Ingrassia, Sezione di Biologia, Genetica, Genomica Cellulare e Molecolare, Unità di BioMedicina Molecolare Genomica e dei Sistemi Complessi, Genetica, Biologia Computazionale, Università di Catania, Via Santa Sofia 87, 95123 Catania, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Scalia
authors.forename: Cristina
authors.initials: C
authors.lastname: Satriano
authors.forename: Rossana
authors.initials: R
authors.lastname: Greca
authors.forename: Anna Maria Giuffrida
authors.initials: AM
authors.lastname: Stella
authors.forename: Enrico
authors.initials: E
authors.lastname: Rizzarelli
authors.forename: Vittoria
authors.initials: V
authors.lastname: Spina-Purrello
mesh_terms: D000893:Anti-Inflammatory Agents; D015415:Biomarkers / Q000378:metabolism; D001932:Brain Neoplasms / Q000473:pathology*; D002336:Carnosine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D015536:Down-Regulation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis; D018613:Microscopy, Confocal; D009573:Nitrites / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013778:Tetrazolium Salts; D013844:Thiazoles; D014199:Trehalose / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D004396:Coloring Agents; D007546:Isoquinolines; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D009573:Nitrites; D010616:Phenanthrenes; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013778:Tetrazolium Salts; D013844:Thiazoles; C108729:3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2H)-isoquinolinone; D002336:Carnosine; D014199:Trehalose; D007770:L-Lactate Dehydrogenase; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C022616:thiazolyl blue