Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization.
Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization.
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DOI：
10.1038/srep23372
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发表时间：
2016-03-18
影响因子：
4.6
通讯作者：
Matsui H
中科院分区：
文献类型：
--
作者：
Hayashi K;Michiue H;Yamada H;Takata K;Nakayama H;Wei FY;Fujimura A;Tazawa H;Asai A;Ogo N;Miyachi H;Nishiki T;Tomizawa K;Takei K;Matsui H
多形性胶质母细胞瘤（GBM）是最常见的恶性脑肿瘤，中位生存时间约为一年。GBM细胞侵入正常脑是导致预后不良的主要原因，需要动态重组肌动蛋白细胞骨架，包括板足突、局灶性粘连和GBM前缘的应力纤维。因此，我们假设肌动蛋白聚合抑制剂可以抑制GBM的迁移和侵袭。首先，我们采用了一种药物重新定位系统，通过基于芘-肌动蛋白的肌动蛋白聚合试验进行筛选，并鉴定出临床使用的抗抑郁药氟伏沙明。氟伏沙明是一种选择性5 -羟色胺再摄取抑制剂，是一种有效的肌动蛋白聚合抑制剂，经证实可穿透血脑屏障（BBB）并在包括脑肿瘤在内的全脑蓄积，无药物毒性。氟伏沙明通过抑制FAK和Akt/雷帕霉素信号的哺乳动物靶点抑制血清诱导的褶皱形成、细胞迁移和体外人GBM和胶质瘤干细胞的侵袭。每日用氟伏沙明治疗携带人胶质瘤起始细胞的胸腺小鼠，在几乎相同剂量的抗抑郁作用下，阻断肿瘤细胞的侵袭，延长生存期。综上所述，氟伏沙明是一种有前景的抗侵袭治疗GBM的可靠方法。
Glioblastoma multiforme (GBM) is the most common malignant brain tumor with a median survival time about one year. Invasion of GBM cells into normal brain is the major cause of poor prognosis and requires dynamic reorganization of the actin cytoskeleton, which includes lamellipodial protrusions, focal adhesions, and stress fibers at the leading edge of GBM. Therefore, we hypothesized that inhibitors of actin polymerization can suppress GBM migration and invasion. First, we adopted a drug repositioning system for screening with a pyrene-actin-based actin polymerization assay and identified fluvoxamine, a clinically used antidepressant. Fluvoxamine, selective serotonin reuptake inhibitor, was a potent inhibitor of actin polymerization and confirmed as drug penetration through the blood–brain barrier (BBB) and accumulation of whole brain including brain tumor with no drug toxicity. Fluvoxamine inhibited serum-induced ruffle formation, cell migration, and invasion of human GBM and glioma stem cells in vitro by suppressing both FAK and Akt/mammalian target of rapamycin signaling. Daily treatment of athymic mice bearing human glioma-initiating cells with fluvoxamine blocked tumor cell invasion and prolonged the survival with almost same dose of anti-depressant effect. In conclusion, fluvoxamine is a promising anti-invasive treatment against GBM with reliable approach.