Perifosine-induced inhibition of Akt attenuates brain-derived neurotrophic factor/TrkB-induced chemoresistance in neuroblastoma in vivo.
Perifosine-induced inhibition of Akt attenuates brain-derived neurotrophic factor/TrkB-induced chemoresistance in neuroblastoma in vivo.
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DOI：
10.1002/cncr.26133
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发表时间：
2011-12-01
期刊：
影响因子：
6.2
通讯作者：
Thiele CJ
中科院分区：
文献类型：
--
作者：
Li Z;Oh DY;Nakamura K;Thiele CJ
神经母细胞瘤(NB)肿瘤表达高水平的脑源性神经营养因子(BDNF)及其受体TrkB或激活的Akt，与神经母细胞瘤患者的无事件或总生存率降低有关。观察Akt抑制剂Perifosine对表达TrkB的神经母细胞瘤细胞或肿瘤化疗敏感性的影响。建立了四环素调控的TrkB表达等基因NB细胞模型系统，并在体外和体内分别用依托泊苷和/或Perifosine处理NB细胞。用Western blotting或激酶活性测定来评价Perifosine对靶细胞的抑制作用。观察细胞存活和肿瘤生长情况。在体外，BDNF诱导Akt的磷酸化，并在TrkB高表达的细胞中挽救依托泊苷诱导的细胞死亡，但在低TrkB表达的细胞中不能。Perifosine可阻断BDNF/TrkB诱导的Akt磷酸化，并阻断BDNF对依托泊苷对高表达TrkB细胞的保护作用。在体内，与TrkB低表达的肿瘤相比，TrkB高表达的肿瘤磷酸化Akt水平升高，并且对依托泊苷治疗的敏感性较低。与单独使用依托泊苷或依托泊苷的小鼠相比，联合使用依托泊苷和依托泊苷的小鼠肿瘤生长显著减少。通过BDNF/TrkB信号通路激活Akt可在体内诱导NB产生化疗耐药。环磷酰胺对Akt的抑制增加了NB对化疗的敏感性。我们的研究支持了Akt抑制剂与细胞毒药物联合用于提高治疗效果的未来临床评估。
Neuroblastoma (NB) tumors expressing high levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB, or activated Akt are associated with decreased event-free or overall survival in neuroblastoma patients. The effect of perifosine, an Akt inhibitor, on chemo-sensitivity of TrkB expressing neuroblastoma cells or tumors was evaluated. A tetracycline-regulated TrkB-expressing isogenic NB cell model system was tested and in this system NB cells were treated with etoposide and/or perifosine in vitro and in vivo. Inhibition of the target by perifosine was evaluated by Western Blotting or kinase activity assay. Cell survival and tumor growth were investigated. In vitro BDNF treatment induced Akt phosphorylation and rescued cells from etoposide-induced cell death in high TrkB-expressing cells, but not in low TrkB-expressing cells. Pretreatment of high TrkB-expressing TB3 cells with perifosine blocked BDNF/TrkB-induced Akt phosphorylation, and inhibited BDNF’s protection of TB3 cells from etoposide treatment. In vivo, tumors with high TrkB expression had elevated levels of phosphorylated Akt, and were less sensitive to etoposide treatment compared to tumors with low TrkB expression. Mice treated with a combination of perifosine and etoposide had a statistically significant decrease of tumor growth compared to mice treated with either etoposide or perifosine alone. Activation of Akt through BDNF/TrkB signaling pathway induced chemo-resistance in NB in vivo. Perifosine-induced inhibition of Akt increased the sensitivity of NB to chemotherapy. Our study supports the future clinical evaluation of an Akt inhibitor combined with cytotoxic drugs for improvement of treatment efficacy.
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影响因子：
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