title: 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: Taipei Medical University, College of Medicine, Graduate Institute of Medical Sciences, Taipei, Taiwan.
authors: Kao-Hui
authors: KH
authors: Liu
authors: Taipei Medical University-Shuang Ho Hospital, Department of Neurosurgery, Taipei, Taiwan.
authors: Shun-Tai
authors: ST
authors: Yang
authors: Taipei Medical University, Biostatistics Center, Taipei, Taiwan.
authors: Yen-Kuang
authors: YK
authors: Lin
authors: Taipei Medical University-Shuang Ho Hospital, Department of Neurosurgery, Taipei, Taiwan.
authors: Jia-Wei
authors: JW
authors: Lin
authors: National Yang-Ming University, Department and Institute of Physiology, Taipei, Taiwan.
authors: Yi-Hsuan
authors: YH
authors: Lee
authors: Taipei Medical University, College of Medicine, Graduate Institute of Medical Sciences, Taipei, Taiwan.|Taipei Medical University, College of Medicine, School of Medicine, Department of Physiology, Taipei, Taiwan.
authors: Jia-Yi
authors: JY
authors: Wang
authors: Taipei Medical University-Shuang Ho Hospital, School of Medicine, Department of Neurology, Taipei, Taiwan.
authors: Chaur-Jong
authors: CJ
authors: Hu
authors: Taipei Medical University Hospital, Department of Neurosurgery, Taipei, Taiwan.
authors: En-Yuan
authors: EY
authors: Lin
authors: Taipei Medical University-Wan Fang Hospital, Department of Neurosurgery, Taipei, Taiwan.
authors: Shu-Mei
authors: SM
authors: Chen
authors: Taipei Medical University, College of Medicine, School of Medicine, Taipei, Taiwan.
authors: Chee-Kin
authors: CK
authors: Then
authors: Taipei Medical University, College of Medicine, Graduate Institute of Medical Sciences, Taipei, Taiwan.
authors: Shing-Chuan
authors: SC
authors: Shen
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival; D005473:Fluoxetine / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D017470:Receptors, Glutamate / Q000378:metabolism*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D018687:Antidepressive Agents, Second-Generation; D017470:Receptors, Glutamate; C492973:alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptor, human; D005473:Fluoxetine; D002118:Calcium
keywords: AMPA receptor; antidepressant; excitotoxicity; glioblastoma