Ibuprofen-induced Walker 256 tumor cell death: cytochrome c release from functional mitochondria and enhancement by calcineurin inhibition.
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.
Campos
Claudia B L
CB
Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP 13083-970, Brazil. cbcampos@fcm.unicamp.br
Degasperi
Giovanna R
GR
Pacífico
Denise S
DS
Alberici
Luciane C
LC
Carreira
Raquel S
RS
Guimarães
Fernando
F
Castilho
Roger F
RF
Vercesi
Anibal E
AE
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
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