Fluoxetine Induces Apoptosis in Ovarian Carcinoma Cell Line OVCAR‐3 Through Reactive Oxygen Species‐Dependent Activation of Nuclear Factor‐κB

Abstract

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)-jB 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-jB) activation] prevented the FLX-induced cell death, increase in phosphorylated inhibitory jB-a and NF-jB p65 levels, and binding of NF-jB 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-jB.

Antidepressant fluoxetine and its potential against colon tumors

“…We have demonstrated that the anti-angiogenic potential of FLX could be related to its control over the differentiation and further transition of endothelial cells through different angiogenesisrelated stem cell markers in colon preneoplastic lesions ated state, which reduces mitochondrial respiratory rate and energy generation [84][85][86] . FLX was also found to induce ROS generation in human ovarian cancer cell lines, which induced apoptosis through mitochondrial bcl-2-associated X protein, cytochrome c release, caspase-3 activation and p53 expression levels, whilst this treatment further reduced ΔΨm, BH3 interacting-domain death agonist and bcl-2 levels [54] . Similar findings were reported in human neuroblastomas [55] .…”

“…In these epithelial cells, it induces an increase in serotonin (5-HT) levels by blocking L-monoamine oxidase and serotonin reuptake transporters [41][42][43] . On the other hand, FLX has been shown to interfere with the OS machinery in experimental models and humans [44][45][46][47][48][49][50][51][52][53][54][55] . Treatment with FLX was found to reduce malondialdehyde (MDA) and carbonyl levels in stressed rats, whilst it enhanced superoxide dismutase (SOD), catalase, glutathione S-transferase, glutathione reductase and glutathione contents [45,46] .…”

“…Comparing those reports that describe how FLX modulates tumor metabolism [49,50,[52][53][54][55] with others describing its activity against tumor growth [40,58,[87][88][89][90][91][92] , it becomes clear that FLX blocks tumor cell proliferation by impairing the malignant energy generation. The anti-tumor proliferative effects of FLX [40,56,92,93] have been related to different causes, such as delays in cell-cycle progression by inhibiting DNA synthesis and also to a possible binding directly to DNA via groove mode and high attraction force [58,[87][88][89][90]94] .…”

Association between antidepressant medication use and epithelial ovarian cancer risk: a systematic review and meta‐analysis of observational studies

“…Increases in endogenous norepinephrine have been shown to induce gonadotropin secretion as well [54,60]. Fluoxetine, a type of SSRI, was demonstrated to induce apoptosis of ovarian carcinoma OVCAR-3 cells [61]. Additionally, other studies have shown that sertraline and paroxetine can inhibit HT29 cells and induce alterations in…”

Emerging anticarcinogenic effects of fluoxetine besides its role in the treatment of breast carcinomas

“…Fluoxetine also exerts its anticarcinogenic effects by modulating the permeability of mitochondrial membranes [4]. As a result, there is increased expression of p53 and a decline in intracellular bcl-2 level along with simultaneous augmentation of levels of Bax.…”