Oncotarget

Research Papers:

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

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 _

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Oncotarget. 2015; 6:5088-5101. doi: 10.18632/oncotarget.3243

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Abstract

Kao-Hui Liu1, Shun-Tai Yang2, Yen-Kuang Lin3, Jia-Wei Lin2, Yi-Hsuan Lee4, Jia-Yi Wang1,5, Chaur-Jong Hu6, En-Yuan Lin7, Shu-Mei Chen8, Chee-Kin Then9 and Shing-Chuan Shen1

1 Taipei Medical University, College of Medicine, Graduate Institute of Medical Sciences, Taipei, Taiwan

2 Taipei Medical University-Shuang Ho Hospital, Department of Neurosurgery, Taipei, Taiwan

3 Taipei Medical University, Biostatistics Center, Taipei, Taiwan

4 National Yang-Ming University, Department and Institute of Physiology, Taipei, Taiwan

5 Taipei Medical University, College of Medicine, School of Medicine, Department of Physiology, Taipei, Taiwan

6 Taipei Medical University-Shuang Ho Hospital, School of Medicine, Department of Neurology, Taipei, Taiwan

7 Taipei Medical University Hospital, Department of Neurosurgery, Taipei, Taiwan

8 Taipei Medical University-Wan Fang Hospital, Department of Neurosurgery, Taipei, Taiwan

9 Taipei Medical University, College of Medicine, School of Medicine, Taipei, Taiwan

Correspondence:

Shing-Chuan Shen, email:

Keywords: glioblastoma, antidepressant, AMPA receptor, excitotoxicity

Received: November 24, 2014 Accepted: December 26, 2014 Published: December 31, 2014

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.

Author Information

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
Primary Contact  _


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