title: Antiproliferative effect of nitrosulindac (NCX 1102), a new nitric oxide-donating non-steroidal anti-inflammatory drug, on human bladder carcinoma cell lines.
abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are potent antitumoral agents but their side effects limit their clinical use. A novel class of drugs, nitric oxide-donating NSAIDs (NO-NSAIDs), was found to be safer and more active than classical NSAIDs. This study explored the effect of the NO-donating sulindac derivative, NCX 1102, on three human urothelial epithelial carcinoma cell lines (T24, 647V, and 1207) and primary cultures of normal urothelial cells. Cytotoxicity, antiproliferative effect, cell cycle alterations, morphological changes, and apoptosis were investigated after treatment with NCX 1102 in comparison with the native molecule. After treatment, there was a cytotoxic effect (with IC(50) at 48 h of 23.1 micro M on 647V, 19.4 micro M on T24, and 14.5 micro M on 1207) and an antiproliferative effect on all three cell lines with NCX 1102 but not with sulindac. No effect was detected on normal urothelial cells. Flow cytometric analysis showed a differential NCX 1102-induced accumulation of cells in various phases of the cell cycle, depending on cell line and concentration. NCX 1102 induced an occurrence of multinucleated cells in all cell lines and mitotic arrest in 647V and 1207. NCX 1102-treated T24 and 647V cell lines showed a significant difference of apoptotic cell amount when compared to controls. Our results demonstrated a greater antiproliferative potency of NCX 1102 compared to its parent molecule sulindac, and suggested that this new NO-NSAID may have therapeutic impact in the management of bladder cancer.
authors.affiliation: Equipe de recherche INSERM E 03-37 Oncogenèse des Tumeurs Respiratoires et Urogénitales, Faculté de Médecine, Créteil, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Huguenin
authors.forename: Francis
authors.initials: F
authors.lastname: Vacherot
authors.forename: Laurence
authors.initials: L
authors.lastname: Kheuang
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Fleury-Feith
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Jaurand
authors.forename: Manlio
authors.initials: M
authors.lastname: Bolla
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Riffaud
authors.forename: Dominique K
authors.initials: DK
authors.lastname: Chopin
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D009569:Nitric Oxide / Q000378:metabolism*; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013997:Time Factors; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; C431582:nitrosulindac; D013467:Sulindac; D009569:Nitric Oxide