TAK1 inhibitor 5Z-7-oxozeaenol sensitizes neuroblastoma to chemotherapy.
TAK1 inhibitor 5Z-7-oxozeaenol sensitizes neuroblastoma to chemotherapy.
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DOI：
10.1007/s10495-013-0864-0
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发表时间：
2013-10
期刊：
影响因子：
7.2
通讯作者：
Yang, Jianhua
中科院分区：
文献类型：
--
作者：
Fan, Yihui;Cheng, Jin;Vasudevan, Sanjeev A.;Patel, Roma H.;Liang, Li;Xu, Xin;Zhao, Yanling;Jia, Wei;Lu, Fengmin;Zhang, Hong;Nuchtern, Jed G.;Kim, Eugene S.;Yang, Jianhua
高危神经母细胞瘤的治疗失败主要是由于化疗耐药的发展。NF-κB活化是癌细胞逃避化疗诱导的细胞死亡的抵抗机制之一。TAK1是基因毒性应激诱导的NF-κB活化的重要组成部分；然而，TAK1在神经母细胞瘤化疗耐药发展中的作用尚不清楚。通过一组神经母细胞瘤细胞系，我们发现TAK1抑制剂5z -7-氧zeaenol显著增强了阿霉素（Dox）和依托泊苷（VP-16）对神经母细胞瘤细胞系的细胞毒性作用。TAK1抑制也增强了Dox和VP-16对非锚定生长的抑制作用。用5z -7-氧玉米烯醇处理神经母细胞瘤细胞可阻断dox -和vp16诱导的NF-κB活化，增强dox -和vp16诱导的细胞凋亡。此外，5z -7-氧zeaenol能够克服LA-N-6神经母细胞瘤细胞中已建立的化学耐药。通过原位神经母细胞瘤小鼠模型，我们发现5z -7-氧玉米烯醇显著提高体内化疗疗效。总之，我们的研究结果提供了一个概念证明，TAK1抑制显着增加神经母细胞瘤细胞对化疗诱导的细胞死亡的敏感性，并且可以作为当前化疗方案的有效辅助治疗高风险疾病。
Treatment failure in high risk neuroblastoma is largely due to development of chemoresistance. NF-κB activation is one of the resistance mechanisms for cancer cells to escape from chemotherapy-induced cell-death. TAK1 is an essential component in genotoxic stresses-induced NF-κB activation; however, the role of TAK1 in the development of chemoresistance in neuroblastoma remains unknown. Using a panel of neuroblastoma cell lines, we found that TAK1 inhibitor 5Z-7-oxozeaenol significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) on neuroblastoma cell lines. TAK1 inhibition also enhanced the inhibitory effect of Dox and VP-16 on anchorage-independent growth. Treatment of neuroblastoma cells with 5Z-7-oxozeaenol blocked Dox-and VP16-induced NF-κB activation and enhanced Dox-and VP16-induced apoptosis. Moreover, 5Z-7-oxozeaenol was able to overcome the established chemoresistance in LA-N-6 neuroblastoma cells. Using an orthotopic neuroblastoma mouse model, we found that 5Z-7-oxozeaenol significantly enhanced chemotherapeutic efficacy in vivo. Together, our results provide a proof-of-concept that TAK1 inhibition significantly increases the sensitivity of neuroblastoma cells to chemotherapy-induced cell-death and can serve as an effective adjunct to current chemotherapeutic regimens for high risk diseases.
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通过PARP-1，需要通过PARP-1进行反馈调节的聚（ADP-核糖基），才能快速响应活细胞中的DNA损伤。
影响因子：
14.9
作者：
Mortusewicz, Oliver;Ame, Jean-Christophe;Schreiber, Valerie;Leonhardt, Heinrich
通讯作者：
Leonhardt, Heinrich
影响因子：
4.8
作者：
Liang L;Fan Y;Cheng J;Cheng D;Zhao Y;Cao B;Ma L;An L;Jia W;Su X;Yang J;Zhang H
通讯作者：
Zhang H
影响因子：
10.3
作者：
Melisi, Davide;Xia, Qianghua;Chiao, Paul J.
通讯作者：
Chiao, Paul J.
影响因子：
4.8
作者：
Ninomiya-Tsuji, J;Kajino, T;Matsumoto, K
通讯作者：
Matsumoto, K
影响因子：
10.5
作者：
Shim, JH;Xiao, CC;Ghosh, S
通讯作者：
Ghosh, S