百憂解應用於治療腦部惡性膠質瘤之研究

The Application of Fluoxetine on High Grade Glioma Treatment

劉高輝(KAO-HUI LIU)

指導教授 ： 沈芯伃

臺北醫學大學/醫學院/醫學科學研究所/博士(2015年)

摘要

無資料

關鍵字

神經膠質瘤 ； 抗憂鬱藥 ； AMPA受體 ； 興奮性細胞毒性

並列摘要

The mean survival time of glioblastoma multiforme (GBM) patients receiving treatment is only about 12~15 months. Most chemotherapeutic drugs commonly used for cancer treatments have low therapeutic potential for GBM, due to their inability to pass through blood-brain barrier and differentiate between normal and tumor cells. 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 Western blotting and a real time-PCR. 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 (TMZ), a first-line GBM chemotherapeutic drug. In contrast, compared to TMZ, fluoxetine had fewer toxic effects on liver function. Our data suggest that fluoxetine can be a safe and useful chemotherapeutic drug for treating GBM.

並列關鍵字

glioblastoma ； antidepressant ； AMPA receptor ； excitotoxicity

參考文獻

1. Omuro A and DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA. 2013; 310: 1842-1850.

2. Watkins S and Sontheimer H. Unique biology of gliomas: challenges and opportunities. Trends Neurosci. 2012; 35: 546-556.

3. Hess KR, Broglio KR and Bondy ML. Adult glioma incidence trends in the United States, 1977-2000. Cancer. 2004; 101: 2293-2299.

4. Preusser M, de Ribaupierre S, Wohrer A, Erridge SC, Hegi M, Weller M and Stupp R. Current concepts and management of glioblastoma. Ann Neurol. 2011; 70: 9-21.

5. 衛生福利部國民健康署. 中華民國100年癌症登記報告. 2014.