Fluoxetine Simultaneously Induces Both Apoptosis and Autophagy in Human Gastric Adenocarcinoma Cells

Abstract

Fluoxetine is used widely as an antidepressant for the treatment of cancer-related depression, but has been reported to also have anti-cancer activity. In this study, we investigated the cytotoxicity of fluoxetine to human gastric adenocarcinoma cells; as shown by the MTT assay, fluoxetine induced cell death. Subsequently, cells were treated with 10 or 20 μM fluoxetine for 24 h and analyzed. Apoptosis was confirmed by the increased number of early apoptotic cells, shown by Annexin V-propidium iodide staining. Nuclear condensation was visualized by DAPI staining. A significant increase in the expression of cleaved PARP was observed by western blotting. The pan-caspase inhibitor Z-VAD-FMK was used to detect the extent of caspase-dependent cell death. The induction of autophagy was determined by the formation of acidic vesicular organelles (AVOs), which was visualized by acridine orange staining, and the increased expression of autophagy markers, such as LC3B, Beclin 1, and p62/SQSTM 1, observed by western blotting. The expression of upstream proteins, such as p-Akt and p-mTOR, were decreased. Autophagic degradation was evaluated by using bafilomycin, an inhibitor of late-stage autophagy. Bafilomycin did not significantly enhance LC3B expression induced by fluoxetine, which suggested autophagic degradation was impaired. In addition, the co-administration of the autophagy inhibitor 3-methyladenine and fluoxetine significantly increased fluoxetine-induced apoptosis, with decreased p-Akt and markedly increased death receptor 4 and 5 expression. Our results suggested that fluoxetine simultaneously induced both protective autophagy and apoptosis and that the inhibition of autophagy enhanced fluoxetine-induced apoptosis through increased death receptor expression.

Modifications of Plasma Membrane Organization in Cancer Cells for Targeted Therapy

“…The anticancer properties of fluoxetine were confirmed in many cancer models, both in vitro and in vivo [98,99]. However, some recent studies support its pro-survival potential as well [100,101]. An example of antiarrhythmic agents that can be potentially used in anticancer therapy is verapamil.…”

Refocusing the Use of Psychiatric Drugs for Treatment of Gastrointestinal Cancers

“…Besides, FLX induces both, protective autophagosome formation and apoptosis simultaneously in vitro. However, autophagy inhibition enhances FLX-induced apoptosis through decrease p-Akt and increase DR4 and DR5 expression (16). Moreover, it has been reported an improved anti-proliferative effect due to FLX/paclitaxel combination on GACs (AGS cell line).…”

Combination of metformin/efavirenz/fluoxetine exhibits profound anticancer activity via a cancer cell-specific ROS amplification

“…34 Furthermore, it has been reported that fluoxetine possesses anticancer activity both in vitro and in vivo . 35 , 36 In addition, fluoxetine enhances the anticancer activity of certain chemotherapeutic anticancer drugs such as gemcitabine and paclitaxel. 37–39 …”