title: Failure of apoptosis and activation on NFkappaB by celecoxib and aspirin in lung cancer cell lines.
abstract: Recent studies have demonstrated that antineoplastic activity of Cox-2 inhibitors may depend on targets other than Cox: among those, nuclear factor kappaB (NFkappaB) seems the most promising. Although preclinical studies have suggested that aspirin and Cox-2 inhibitors may influence the progression of lung cancer, the molecular mechanisms of these protective effects in this tumor type has not been fully elucidated. We investigated the effects of celecoxib and aspirin in the induction of apoptosis and in the ability to activate NFkappaB in three non-small cell lung cancer cell lines. Apoptosis was evaluated by FACS, caspase activation assay and expression of apoptosis-related genes by RT-PCR, while NFkappaB activation was assessed by immunofluorescence. No apoptotic response was observed after treatment with both high and low dose of celecoxib. Nevertheless, celecoxib at both concentrations induced a strong NFkappaB activation, with increased expression of NFkappaB-dependent genes, such as bcl-2, bcl-XL and survivin. Similarly, aspirin at both concentrations did not induce any apoptotic response, but activated NFkappaB in a dose-dependent manner. This study supports the hypothesis that NFkappaB activation is an important effect of NSAIDs in lung cancer, leading to apoptosis resistance. This effect of both aspirin and celecoxib may be considered undesirable in lung cancer chemoprevention.
authors.affiliation: Department of Experimental Medicine and Pathology, University of the Study of Rome 'La Sapienza', 00161 Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Gradilone
authors.forename: Ida
authors.initials: I
authors.lastname: Silvestri
authors.forename: Susanna
authors.initials: S
authors.lastname: Scarpa
authors.forename: Stefania
authors.initials: S
authors.lastname: Morrone
authors.forename: Orietta
authors.initials: O
authors.lastname: Gandini
authors.forename: Fabio M
authors.initials: FM
authors.lastname: Pulcinelli
authors.forename: Walter
authors.initials: W
authors.lastname: Gianni
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Aglianò
authors.forename: Paola
authors.initials: P
authors.lastname: Gazzaniga
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000494:pharmacology*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D002470:Cell Survival; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000737:chemistry / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D000077022:Survivin; D051996:Transcription Factor RelA / Q000032:analysis; D015854:Up-Regulation; D051020:bcl-X Protein / Q000235:genetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C107489:BIRC5 protein, human; D016861:Cyclooxygenase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D013449:Sulfonamides; D000077022:Survivin; D051996:Transcription Factor RelA; D051020:bcl-X Protein; D000068579:Celecoxib; D001241:Aspirin