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 a-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.

Original languageEnglish
Pages (from-to)5088-5101
Number of pages14
JournalOncotarget
Volume6
Issue number7
Publication statusPublished - 2015

Fingerprint

Fluoxetine
Glioblastoma
Antidepressive Agents
Apoptosis
Calcium
Glioma
temozolomide
Poisons
Therapeutic Uses
Animal Models
Quality of Life
Staining and Labeling
Drug Therapy
Polymerase Chain Reaction
Acids
Incidence
Brain
Growth

Keywords

  • AMPA receptor
  • Antidepressant
  • Excitotoxicity
  • Glioblastoma

ASJC Scopus subject areas

  • Oncology

Cite this

Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis. / Liu, Kao Hui; Yang, Shun Tai; Lin, Yen-Kuang; Lin, Jia Wei; Lee, Yi Hsuan; Wang, Jia Yi; Hu, Chaur Jong; Lin, En Yuan; Chen, Shu Mei; Then, Chee Kin; Shen, Shing Chuan.

In: Oncotarget, Vol. 6, No. 7, 2015, p. 5088-5101.

Research output: Contribution to journalArticle

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