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.

• Authors: Kao-Hui Liu, Shun-Tai Yang, Yen-Kuang Lin, Jia-Wei Lin, Yi-Hsuan Lee, Jia-Yi Wang, Chaur-Jong Hu, En-Yuan Lin, Shu-Mei Chen, Chee-Kin Then, Shing-Chuan Shen
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 7 Pg. 5088-101 (Mar 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25671301 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antidepressive Agents, Second-Generation
• Receptors, Glutamate
• alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptor, human
• Fluoxetine
• Calcium

Topics

• Animals
• Antidepressive Agents, Second-Generation (pharmacology)
• Apoptosis (drug effects)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Calcium (metabolism)
• Cell Survival
• Fluoxetine (pharmacology)
• Glioblastoma (drug therapy, metabolism, pathology)
• Humans
• Male
• Mice
• Mice, Nude
• Molecular Docking Simulation
• Receptors, Glutamate (metabolism)
• Treatment Outcome
• Xenograft Model Antitumor Assays