Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis
| Autor: | Chaur Jong Hu, Shun Tai Yang, Yi Hsuan Lee, Shu Mei Chen, Yen Kuang Lin, Shing Chuan Shen, Jia Wei Lin, Jia Yi Wang, Kao Hui Liu, Chee Kin Then, En Yuan Lin |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty Neurology Cell Survival Mice Nude Apoptosis AMPA receptor Biology Pharmacology Mice Fluoxetine Glioma medicine Animals Humans antidepressant Temozolomide Brain Neoplasms glioblastoma medicine.disease Xenograft Model Antitumor Assays humanities Molecular Docking Simulation Treatment Outcome Receptors Glutamate Oncology Antidepressive Agents Second-Generation Antidepressant Calcium excitotoxicity Research Paper medicine.drug Glioblastoma |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Kao-Hui Liu 1 , Shun-Tai Yang 2 , Yen-Kuang Lin 3 , Jia-Wei Lin 2 , Yi-Hsuan Lee 4 , Jia-Yi Wang 1,5 , Chaur-Jong Hu 6 , En-Yuan Lin 7 , Shu-Mei Chen 8 , Chee-Kin Then 9 and Shing-Chuan Shen 1 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 Ca 2+ influx. The rise in the intracellular calcium concentration ([Ca 2+ ] i ) causes mitochondrial Ca 2+ 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|