Fluoxetine induces apoptosis in ovarian carcinoma cell line OVCAR-3 through reactive oxygen species-dependent activation of nuclear factor-kappaB.
The apoptotic effect of fluoxetine (FLX), an antidepressant, against human epithelial ovarian cancer cell lines OVCAR-3 and SK-OV-3 was investigated in relation to the mitochondria-mediated cell death process and nuclear factor (NF)-kappaB activation. FLX-induced mitochondrial membrane permeability change and formation of reactive oxygen species, leading to cell death. FLX-induced increase in mitochondrial Bax levels, decrease in cytosolic Bid and Bcl-2 levels, loss of the mitochondrial transmembrane potential, cytochrome c release, caspase-3 activation and up-regulation of p53. Oxidant scavengers and Bay 11-7085 [an inhibitor of nuclear factor kappaB (NF-kappaB) activation] prevented the FLX-induced cell death, increase in phosphorylated inhibitory kappaB-alpha and NF-kappaB p65 levels, and binding of NF-kappaB p65 to DNA. Results from this study suggest that FLX may exhibit apoptotic effect against ovarian cancer cell lines by inducing the mitochondrial membrane permeability change, which leads to cytochrome c release and subsequent caspase-3 activation, through reactive oxygen species-dependent activation of NF-kappaB.
Lee
Chung Soo
CS
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, South Korea. leecs@cau.ac.kr
Kim
Yun Jeong
YJ
Jang
Eun Ra
ER
Kim
Wonyong
W
Myung
Soon Chul
SC
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D053148:Caspase 3; D045304:Cytochromes c; D005473:Fluoxetine; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D017367:Selective Serotonin Reuptake Inhibitors