Differential induction of apoptosis by antidepressants in glioma and neuroblastoma cell lines - Evidence for p-c-Jun, cytochrome c, and caspase-3 involvement
Differential induction of apoptosis by antidepressants in glioma and neuroblastoma cell lines - Evidence for p-c-Jun, cytochrome c, and caspase-3 involvement
复制标题
DOI：
10.1385/jmn:27:1:029
复制
发表时间：
2005-01-01
影响因子：
3.1
通讯作者：
Weizman, A
中科院分区：
文献类型：
--
作者：
Levkovitz, Y;Gil-Ad, I;Weizman, A
几种抗抑郁药，主要是选择性血清素再摄取抑制剂（SSRIs）和一些三环抗抑郁药（TCAs），已被证明在不同细胞系中具有强效的凋亡活性。我们的目的是筛选和选择那些具有显著活性的药物，并阐明大鼠胶质瘤和人类神经母细胞瘤细胞系中这一过程的分子途径。我们研究了不同抗抑郁药对凋亡标志物的影响，包括：细胞活力、DNA断裂、线粒体细胞色素c （Cyt c）释放和caspase-3样活性。此外，还确定了MAPK基因、c-Jun和ERK的参与情况。通过碘化丙啶染色C6细胞的流式细胞术和胶质瘤细胞的典型荧光显微镜评估，帕罗西汀和氟西汀、SSRIs、氯丙咪嗪（一种TCA），而不是丙咪嗪或米安色林（一种非典型抗抑郁药），在这两种细胞系中引起细胞凋亡。在这些凋亡变化之前，p-c-Jun水平迅速增加，线粒体释放Cyt -c， caspase-3样活性增加。帕罗西汀对原代小鼠大脑和神经元的细胞毒性评估显示，该药对促凋亡活性的敏感性显著降低。这些结果强烈表明，选定的抗抑郁药可诱导神经元和神经胶质细胞系凋亡。p-c-jun的激活和随后Cyt -c线粒体释放的增加参与了抗抑郁药的凋亡机制。与原发脑组织相比，癌细胞对这些药物的高敏感性表明，这些药物可能用于治疗脑源性肿瘤。
Several antidepressants, mainly selective serotonin-reuptake inhibitors (SSRIs) and some tricyclic antidepressants (TCAs), have been shown to possess potent apoptotic activity in different cell lines. Our aim was to screen and select those agents with significant activity and elucidate the molecular pathway underlying this process in rat glioma and human neuroblastoma cell lines. We studied the effect of different antidepressants on apoptotic markers, including: cell viability, DNA fragmentation, cytochrome c (Cyt c) release from mitochondria, and caspase-3-like activity. In addition, the involvement of MAPK genes, c-Jun, and ERK was determined. Paroxetine and fluoxetine, SSRIs, clomipramine, a TCA, but not imipramine or mianserin (an atypical antidepressant), caused apoptosis in both cell lines, as assessed by flow cytometry of propidium iodide-stained C6 cells and typical fluorescence microscopy in glioma cells. These apoptotic changes were preceded by rapid increase in p-c-Jun levels, Cyt c release from mitochondria, and increased caspase-3-like activity. Assessment of paroxetine cytotoxicity in primary mouse brain and neuronal cultures showed significantly lower sensitivity to the drug's proapoptotic activity. These results strongly suggest that selected antidepressants induce apoptosis in neuronal and glial cell lines. Activation of p-c-jun and subsequent increased Cyt c mitochondrial release participate in the apoptotic mechanism of the antidepressant. The high sensitivity to these drugs of the cancer cell, compared with primary brain tissue, suggests the potential use of these agents in the treatment of brain-derived tumors.