title: Effects of simvastatin on cell viability and proinflammatory pathways in lung adenocarcinoma cells exposed to hydrogen peroxide.
abstract: Lung cancer is characterized by a high mortality rate probably attributable to early metastasis. Oxidative stress is involved in development and progression of lung cancer, through cellular and molecular mechanisms which at least in part overlap with proinflammatory pathways. Simvastatin is a statin with pleiotropic effects that can also act as an anti-oxidant agent, and these pharmacologic properties may contribute to its potential anti-cancer activity. Therefore, the aim of this study was to evaluate, in the human lung adenocarcinoma cell line GLC-82, the effects of a 24-hour treatment with simvastatin on hydrogen peroxide (H2O2)-induced changes in cell viability, ERK phosphorylation, matrix metalloproteinase (MMP) expression, innate immunity signaling, NF-κB activation and IL-8 secretion. Cell counting was performed after trypan blue staining, cell proliferation was assessed using MTT assay, and apoptosis was evaluated through caspase-3 activation and Tunel assay. Western blotting was used to analyze protein extracts, and IL-8 release into cell culture supernatants was assessed by ELISA. Our results show that simvastatin (30 μM) significantly (P <0.01) inhibited the proliferative effect of H2O2 (0.5 mM) and its stimulatory actions on ERK1/2 phosphorylation, NF-κB activation and IL-8 production. Furthermore, simvastatin decreased H2O2-mediated induction of the cellular expression of MMP-2 and MMP-9, as well as of several components of the signaling complex activated by innate immune responses, including MyD88, TRAF2, TRAF6 and TRADD. In conclusion, these findings suggest that simvastatin could play a role in prevention and treatment of lung cancer via modulation of important proinflammatory and tumorigenic events promoted by oxidative stress.
authors.forename: Luca
authors.initials: L
authors.lastname: Gallelli
authors.forename: Daniela
authors.initials: D
authors.lastname: Falcone
authors.forename: Monica
authors.initials: M
authors.lastname: Scaramuzzino
authors.forename: Girolamo
authors.initials: G
authors.lastname: Pelaia
authors.affiliation: Department of Experimental Medicine-Section of Pharmacology, School of Medicine, Second University of Naples, via Costantinopoli 16, 80136 Naples, Italy. bruno.dagostino@unina2.it.
authors.forename: Bruno
authors.initials: B
authors.lastname: D'Agostino
authors.forename: Maria
authors.initials: M
authors.lastname: Mesuraca
authors.forename: Rosa
authors.initials: R
authors.lastname: Terracciano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Spaziano
authors.forename: Rosario
authors.initials: R
authors.lastname: Maselli
authors.forename: Michele
authors.initials: M
authors.lastname: Navarra
authors.forename: Rocco
authors.initials: R
authors.lastname: Savino
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016209:Interleukin-8; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C115460:RECK protein, human; D053199:TNF Receptor-Associated Death Domain Protein; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D019821:Simvastatin; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9