title: Ibuprofen-induced Walker 256 tumor cell death: cytochrome c release from functional mitochondria and enhancement by calcineurin inhibition.
abstract: The participation of mitochondria in the mechanism of tumor cell death induced by non-steroid anti-inflammatory drugs is uncertain. Here we show that ibuprofen induces death of Walker 256 tumor cells independently on mitochondrial depolarization as estimated by flow cytometry using DioC(6)(3). Oligomycin increased mitochondrial transmembrane potential in both ibuprofen-treated and non-treated cells, indicating that ATP synthesis was sustained during cell death. Cyclosporin A, but not bongkrekic acid, both mitochondrial permeability transition inhibitors, increased the percentage of cell death in the presence of ibuprofen. FK506, a calcineurin inhibitor like cyclosporin A, also increased ibuprofen-induced cell death. Moreover, we showed that cytochrome c was released during ibuprofen-induced cell death. In conclusion, death of Walker 256 tumor cells induced by ibuprofen does not impair mitochondrial function, involves cytochrome c release and is accompanied by a rescue pathway via calcineurin activation.
authors.affiliation: Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP 13083-970, Brazil. cbcampos@fcm.unicamp.br
authors.forename: Claudia B L
authors.initials: CB
authors.lastname: Campos
authors.forename: Giovanna R
authors.initials: GR
authors.lastname: Degasperi
authors.forename: Denise S
authors.initials: DS
authors.lastname: Pacífico
authors.forename: Luciane C
authors.initials: LC
authors.lastname: Alberici
authors.forename: Raquel S
authors.initials: RS
authors.lastname: Carreira
authors.forename: Fernando
authors.initials: F
authors.lastname: Guimarães
authors.forename: Roger F
authors.initials: RF
authors.lastname: Castilho
authors.forename: Anibal E
authors.initials: AE
authors.lastname: Vercesi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D065095:Calcineurin Inhibitors; D016923:Cell Death / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism*; D006868:Hydrolysis; D007052:Ibuprofen / Q000494:pharmacology*; D007473:Ion Channels / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D051381:Rats; D012119:Respiration; D016559:Tacrolimus / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D065095:Calcineurin Inhibitors; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D007052:Ibuprofen; D016559:Tacrolimus