Combined inhibition of AKT/mTOR and MDM2 enhances Glioblastoma Multiforme cell apoptosis and differentiation of cancer stem cells.
Combined inhibition of AKT/mTOR and MDM2 enhances Glioblastoma Multiforme cell apoptosis and differentiation of cancer stem cells.
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AKT/mTOR 和 MDM2 的联合抑制可增强多形性胶质母细胞瘤细胞凋亡和癌症干细胞的分化。
DOI：
10.1038/srep09956
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发表时间：
2015-04-21
影响因子：
4.6
通讯作者：
Martini C
中科院分区：
文献类型：
--
作者：
Daniele S;Costa B;Zappelli E;Da Pozzo E;Sestito S;Nesi G;Campiglia P;Marinelli L;Novellino E;Rapposelli S;Martini C
多形性胶质母细胞瘤(GBM)预后差的原因是对常规治疗的高度抵抗和胶质瘤干细胞(GSCs)亚群的存在。针对GBM和GSCs存活/自我更新信号的联合治疗正在成为改善GBM治疗的有用工具。在这种背景下，高活性的AKT/哺乳动物雷帕霉素靶标(AKT/mTOR)和被抑制的野生型p53似乎是很好的候选者。在这里，使用新的AKT/mTOR抑制剂FC85和ISA27来研究这些通路之间的相互作用，ISA27通过阻断其内源性抑制物小鼠双分钟2同源物(MDM2)来重新激活P53功能。在GBM细胞中，FC85有效地抑制AKT/mTOR信号转导，重新激活P53功能，引发细胞凋亡。ISA27联合应用对抑制细胞活力和重新激活P53通路有协同作用。最重要的是，FC85和ISA27抑制了GSC的增殖，促进了GSC的分化。同时使用这些化合物可显著促进GSC的分化/凋亡。这些发现表明，FC85积极增强下游的P53信号，旨在抑制AKT/mTOR通路和重新激活P53信号的组合策略在GBM和GSC中可能是有效的。
The poor prognosis of Glioblastoma Multiforme (GBM) is due to a high resistance to conventional treatments and to the presence of a subpopulation of glioma stem cells (GSCs). Combination therapies targeting survival/self-renewal signals of GBM and GSCs are emerging as useful tools to improve GBM treatment. In this context, the hyperactivated AKT/mammalian target of the rapamycin (AKT/mTOR) and the inhibited wild-type p53 appear to be good candidates. Herein, the interaction between these pathways was investigated, using the novel AKT/mTOR inhibitor FC85 and ISA27, which re-activates p53 functionality by blocking its endogenous inhibitor murine double minute 2 homologue (MDM2). In GBM cells, FC85 efficiently inhibited AKT/mTOR signalling and reactivated p53 functionality, triggering cellular apoptosis. The combined therapy with ISA27 produced a synergic effect on the inhibition of cell viability and on the reactivation of p53 pathway. Most importantly, FC85 and ISA27 blocked proliferation and promoted the differentiation of GSCs. The simultaneous use of these compounds significantly enhanced GSC differentiation/apoptosis. These findings suggest that FC85 actively enhances the downstream p53 signalling and that a combination strategy aimed at inhibiting the AKT/mTOR pathway and re-activating p53 signalling is potentially effective in GBM and in GSCs.
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影响因子：
4.8
作者：
Fernando, P;Brunette, S;Megeney, LA
通讯作者：
Megeney, LA
影响因子：
2.6
作者：
Lv, Kai;Wang, Li-Li;Li, Song
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Li, Song
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7.3
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影响因子：
3.4
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Mendiburu-Elicable, M.;Gil-Ranedo, J.;Izquierdo, M.
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Izquierdo, M.
影响因子：
4.2
作者：
Friedman, Marissa D.;Jeevan, Dhruve S.;Jhanwar-Uniyal, Meena
通讯作者：
Jhanwar-Uniyal, Meena