Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

Abstract

The efficacy of glioblastoma chemotherapy is not satisfactory; therefore, a new medication is expected to improve outcomes. As much evidence shows that antidepressants decrease cancer incidence and improve patients' quality of life, we therefore attempted to explore the potential for fluoxetine to be used to treat GBM and its possible underlying mechanism. The expression level of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was determined using immunohistochemical staining and PCR analysis. The mechanism of fluoxetine-induced apoptosis of gliomas was elucidated. Computer modeling and a binding assay were conducted to investigate the interaction of fluoxetine with the AMPAR. The therapeutic effect of fluoxetine was evaluated using an animal model. We found that fluoxetine directly bound to AMPAR, thus inducing transmembrane Ca2+ influx. The rise in the intracellular calcium concentration ([Ca2+]i) causes mitochondrial Ca2+ overload, thereby triggering apoptosis. AMPARs are excessively expressed in glioma tissues, suggesting that fluoxetine specifically executes glioma cells. Our in vivo study revealed that fluoxetine suppressed the growth of glioblastomas in brains of Nu/Nu mice, an effect similar to that produced by temozolomide. Our preclinical studies suggest fluoxetine, a commonly used antidepressant, might be selectively toxic to gliomas and could provide a new approach for managing this disease.

Fluoxetine regulates cell growth inhibition of interferon-α

“…In addition, the dosage of fluoxetine as a chemosensitizer is kept under the range of 5-20 µM, where this agent itself does not affect cell viability (15). In the present study, fluoxetine at 10 µM did not induce apoptosis, whereas higher concentrations of fluoxetine (>25 µM) could suppress glioblastoma cells by calcium-dependent apoptosis (31). Alternatively, the addition of fluoxetine lessened the IFN-α-induced apoptosis but switched to cause G1 arrest, and maintained the IFN-α-mediated reduction in G2/M phase (Fig.…”

SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKIIγ/AKT-mediated pathway

“…Growing evidence supports the contribution of altered Ca 2+ signaling to tumor progression and metastasis, suggesting that agents targeting calcium influx and calcium influx-driven downstream signaling may hopefully offer alternative approaches for cancer therapy [17,18]. Several calcium channels blockers have been investigated in clinical trials [19–21]; however, their efficacy has not been satisfactory for unclear reasons.…”

Fluoxetine Maintains a State of Heightened Responsiveness to Motor Training Early After Stroke in a Mouse Model

“…57 It is also possible that the increased cell death in mice receiving fluoxetine (Figure 3A) played a role in the initial poorer performance. Although most studies have indicated that SSRIs tend to potentiate cell survival, a few have demonstrated fluoxetine-induced growth factor reduction 58 as well as SSRI-induced apoptosis, especially of diseased cells, 59–62 perhaps by potentiation of the immune system. 63 Nevertheless, despite increased cell death, animals receiving fluoxetine eventually outperformed animals receiving saline.…”