FTY720 诱导脑肿瘤干细胞凋亡：胶质母细胞瘤的潜在治疗药物。
Induction of brain tumor stem cell apoptosis by FTY720: a potential therapeutic agent for glioblastoma.
机构信息
Department of Pathology, The Ohio State University, Columbus, Ohio, USA.
出版信息
Neuro Oncol. 2012 Apr;14(4):405-15. doi: 10.1093/neuonc/nos005. Epub 2012 Feb 20.
Abstract
FTY720 is a sphingosine analogue that down regulates expression of sphingosine-1-phosphate receptors and causes apoptosis of multiple tumor cell types, including glioma cells. This study examined the effect of FTY720 on brain tumor stem cells (BTSCs) derived from human glioblastoma (GBM) tissue. FTY720 treatment of BTSCs led to rapid inactivation of ERK MAP kinase, leading to upregulation of the BH3-only protein Bim and apoptosis. In combination with temozolomide (TMZ), the current standard chemotherapeutic agent for GBM, FTY720 synergistically induced BTSC apoptosis. FTY720 also slowed growth of intracranial xenograft tumors in nude mice and augmented the therapeutic effect of TMZ, leading to enhanced survival. Furthermore, the combination of FTY720 and TMZ decreased the invasiveness of BTSCs in mouse brains. FTY720 is known to cross the blood-brain barrier and recently received Food and Drug Administration approval for treatment of relapsing multiple sclerosis. Thus, FTY720 is an excellent potential therapeutic agent for treatment of GBM.
摘要
FTY720 是一种鞘氨醇类似物，可下调鞘氨醇-1-磷酸受体的表达，并导致多种肿瘤细胞类型，包括神经胶质瘤细胞发生凋亡。本研究探讨了 FTY720 对源自人神经胶质瘤（GBM）组织的脑肿瘤干细胞（BTSC）的影响。FTY720 处理 BTSC 可导致 ERK MAP 激酶迅速失活，导致 BH3 仅蛋白 Bim 的上调和凋亡。与替莫唑胺（TMZ）联合使用，TMZ 是 GBM 的当前标准化疗药物，FTY720 协同诱导 BTSC 凋亡。FTY720 还可减缓裸鼠颅内异种移植肿瘤的生长，并增强 TMZ 的治疗效果，从而提高存活率。此外，FTY720 和 TMZ 的联合使用可降低 BTSC 在小鼠大脑中的侵袭性。FTY720 已知可穿透血脑屏障，最近获得美国食品和药物管理局批准用于治疗复发性多发性硬化症。因此，FTY720 是治疗 GBM 的一种极好的潜在治疗剂。
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