Second-generation proteasome inhibitor carfilzomib sensitizes neuroblastoma cells to doxorubicin-induced apoptosis.
Second-generation proteasome inhibitor carfilzomib sensitizes neuroblastoma cells to doxorubicin-induced apoptosis.
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DOI：
10.18632/oncotarget.12427
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发表时间：
2016-11-15
期刊：
影响因子：
--
通讯作者：
Yang J
中科院分区：
文献类型：
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作者：
Guan S;Zhao Y;Lu J;Yu Y;Sun W;Mao X;Chen Z;Xu X;Pan J;Sun S;Yang J
神经母细胞瘤（NB）是儿童最常见的颅外恶性肿瘤，约占儿童癌症相关死亡率的15%。蛋白酶体活性水平的升高促进癌症的发展，并且蛋白酶体活性的抑制是用于癌症治疗的有前景的策略。因此，通过小分子抑制剂靶向蛋白酶体可能是NB治疗的可行选择。在这项研究中，我们发现一种新的蛋白酶体抑制剂Carfilzalpine（CFZ）对NB具有抗肿瘤作用。CFZ导致NB细胞系的一个子集的细胞活力降低和集落形成能力减弱。CFZ诱导NB细胞凋亡。此外，CFZ增强阿霉素（Dox）对NB细胞的细胞毒作用和Dox诱导的p38和JNK磷酸化。此外，CFZ通过稳定IκBα蛋白水平，抑制Dox诱导的NF-κB活化。此外，在原位异种移植小鼠模型中，CFZ诱导NB肿瘤细胞凋亡并增强Dox诱导的NB肿瘤细胞凋亡。总之，我们的研究表明，蛋白酶体是一个治疗目标，在NB和蛋白酶体抑制CFZ是一个潜在的治疗策略，治疗NB患者。
Neuroblastoma (NB), which accounts for about 15% of cancer-related mortality in children, is the most common extracranial malignant neoplasm in children. Elevated level of proteasome activity promotes cancer development and the inhibition of proteasome activity is a promising strategy for cancer treatment. Therefore, targeting proteasome by small molecule inhibitors may be a viable option for NB therapy. Here in this study, we show that a novel proteasome inhibitor Carfilzomib (CFZ) exerts anti-tumor effect on NB. CFZ caused decreased cell viability and attenuated colony formation ability of a subset of NB cell lines. CFZ induced cell apoptosis in NB cells. Moreover, CFZ enhanced the cytotoxic effect of doxorubicin (Dox) on NB cells and Dox-induced p38 and JNK phosphorylation. In addition, CFZ inhibited Dox-induced NF-κB activation by stabilizing the protein level of IκBα. Furthermore, CFZ induced apoptosis and augmented Dox-induced apoptosis in NB tumor cells in orthotopic xenograft mouse models. In summary, our study suggests that proteasome is a therapeutic target in NB and proteasome inhibition by CFZ is a potential therapeutic strategy for treating NB patients.