title: Uncoupling of oxidative phosphorylation and Smac/DIABLO release are not sufficient to account for induction of apoptosis by sulindac sulfide in human colorectal cancer cells.
abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) have shown chemopreventive properties in colorectal cancer, involving both cyclooxygenase (COX)-dependent and -independent mechanisms. Apart from their selectivity for COX isoenzymes, NSAIDs differ in their acidic character which supports ability to uncouple oxidative phosphorylation. To assess the possible contribution of uncoupling to their antineoplastic properties, we compared the effect of sulindac sulfide (SS), an acidic NSAID and NS-398, a non-acidic tricyclic, on mitochondrial function and apoptosis in colorectal cancer cell lines (HT29, Caco-2, HCT15 and HCT116). Although cell lines displayed a different COX status, SS and NS-398 caused growth arrest in a dose-related manner. High dose (10(-4)M) of SS but not of NS-398, increased the percentage of subG1 cell population while reducing mitochondrial transmembrane potential (DeltaPsim). Cyclosporin A (CsA, 1 microM) prevented collapse of DeltaPsim induced by 10(-4)M SS but not by 7.5 microM FCCP used as a protonophoric control. SS and FCCP increased the cytosolic release of Smac/DIABLO which was differently affected by CsA pretreatment depending on the uncoupler. Finally, 7.5 microM FCCP failed to induce apoptosis whereas CsA prevented apoptosis induced by SS from 16% in HCT15 to 41% in HCT116. The present study shows that despite the ability of sulindac sulfide to behave as a protonophoric uncoupler, CsA-sensitive opening of mitochondrial permeability transition pore contributes little to its pro-apoptotic effect in colorectal cancer cells.
authors.affiliation: Laboratoire de Physiopathologie et Pharmacologie Articulaires, UMR 7561 CNRS-UHP, Faculté de Médecine, Université Henri Poincaré, 54 505 Vandoeuvre-lès-Nancy cedex, France.
authors.forename: Mikael
authors.initials: M
authors.lastname: Daouphars
authors.forename: Meriem
authors.initials: M
authors.lastname: Koufany
authors.forename: Alexandre
authors.initials: A
authors.lastname: Benani
authors.forename: Sophie
authors.initials: S
authors.lastname: Marchal
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Merlin
authors.forename: Patrick
authors.initials: P
authors.lastname: Netter
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Jouzeau
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D018890:Chemoprevention; D015179:Colorectal Neoplasms / Q000473:pathology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D013449:Sulfonamides / Q000494:pharmacology; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; D014475:Uncoupling Agents; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D013467:Sulindac; C025462:sulindac sulfide