title: Molecular characterization of cytotoxic and resistance mechanisms induced by NCX 4040, a novel NO-NSAID, in pancreatic cancer cell lines.
abstract: Although non steroidal antiinflammatory drugs (NSAIDs) have been shown to be effective as chemopreventive agents, important side-effects limit their clinical use. A promising novel class of drugs, nitric oxide-donating NSAIDs (NO-NSAIDs), has been found to be more active than classical NSAIDs. This study explored the effect of the NO-donating aspirin derivative, NCX 4040, on three human pancreatic adenocarcinoma cell lines (Capan-2, MIA PaCa-2 and T3M4). NCX 4040 activity was compared with that of NCX 4016 (an NO(2)-positional isomer of NCX 4040), SNAP (a standard NO-releasing molecule), NCX 4042 (denitrated analog of NCX 4040), and aspirin. NCX 4040 showed a striking cytocidal activity in all cell lines, already inducing significant percentages of apoptotic cells at 10 muM in Capan-2 cell lines. This study focused on the biological mechanisms of sensitivity and resistance to NCX 4040, highlighting that the cytotoxic action of this drug may be due to the hyperexpression of Bax, its translocation to the mitochondria, the release of Cytochrome C, and the activation of caspases-9 and -3, overall in a p53-independent manner. Moreover, the use of a specific COX-2 inhibitor (NS 398) in the experimental models showed that COX-2 hyperexpression could partially explain the resistance mechanisms to NCX 4040.
authors.affiliation: Istituto Oncologico Romagnolo, Meldola, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rosetti
authors.forename: Anna
authors.initials: A
authors.lastname: Tesei
authors.forename: Paola
authors.initials: P
authors.lastname: Ulivi
authors.forename: Francesco
authors.initials: F
authors.lastname: Fabbri
authors.forename: Ivan
authors.initials: I
authors.lastname: Vannini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Brigliadori
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.forename: Manlio
authors.initials: M
authors.lastname: Bolla
authors.forename: Wainer
authors.initials: W
authors.lastname: Zoli
mesh_terms: D000230:Adenocarcinoma; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000031:analogs & derivatives* / Q000494:pharmacology; D053453:Caspase 9 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009574:Nitro Compounds / Q000494:pharmacology*; D010190:Pancreatic Neoplasms; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D012459:Salicylates / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003603:Cytotoxins; C498045:NCX 4040; C507361:NCX 4042; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D012459:Salicylates; D026423:S-Nitroso-N-Acetylpenicillamine; D053453:Caspase 9; C102148:nitroaspirin; D001241:Aspirin