Homoharringtonine interacts synergistically with bortezomib in NHL cells through MCL-1 and NOXA-dependent mechanisms.
Homoharringtonine interacts synergistically with bortezomib in NHL cells through MCL-1 and NOXA-dependent mechanisms.
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DOI：
10.1186/s12885-018-5018-x
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发表时间：
2018-11-16
期刊：
影响因子：
3.8
通讯作者：
Grant S
中科院分区：
文献类型：
--
作者：
Nguyen T;Parker R;Zhang Y;Hawkins E;Kmieciak M;Craun W;Grant S
在DLBCL和套细胞淋巴瘤细胞（MCL）中，研究了蛋白合成抑制剂同哈林丁碱（HHT）和蛋白酶体抑制剂硼替佐米的相互作用。将HHT和硼替佐米单独或共同作用于不同的DLBCL和MCL细胞，流式细胞术和Western blot检测细胞凋亡和信号通路的变化。异种移植小鼠模型用于评估肿瘤生长和动物存活。HHT和硼替佐米联合给药可协同诱导GC-、ABC-和双击DLBCL细胞凋亡。在MCL细胞和原发性淋巴瘤细胞中观察到类似的相互作用。HHT/硼替佐米联合给药减少了MCL-1与BAK和NOXA的结合。NOXA敲低可显著降低细胞的致死率，而MCL-1敲低或异位NOXA表达可增加细胞死亡。值得注意的是，在BAK敲除或敲除细胞中，HHT/硼替佐米的致病性显著降低。最后，在GC-和ABC-异种移植模型中，与单药相比，HHT/硼替佐米联合给药显著提高了生存率，同时毒性很小。这些发现表明，HHT和硼替佐米通过MCL-1下调、NOXA上调和BAK激活等过程共同杀伤DLBCL和MCL细胞。他们还建议在DLBCL和MCL中，HHT联合硼替佐米的策略值得关注。本文的在线版本（10.1186/s12885-018-5018-x）包含补充资料，仅供授权用户使用。
Interactions between the protein synthesis inhibitor homoharringtonine (HHT) and the proteasome inhibitor bortezomib were investigated in DLBCL and mantle cell lymphoma cells (MCL). Various DLBCL and MCL cells were exposed to HHT and bortezomib alone or together after which apoptosis and signaling pathway perturbations were monitored by flow cytometry and Western blot analysis. Xenograft mouse models were used to assess tumor growth and animal survival. HHT and bortezomib co-administration synergistically induced apoptosis in GC-, ABC- and double-hit DLBCL cells. Similar interactions were observed in MCL cells and in primary lymphoma cells. HHT/bortezomib co-administration diminished binding of MCL-1 to both BAK and NOXA. Knock-down of NOXA significantly diminished lethality whereas MCL-1 knock-down or ectopic NOXA expression increased cell death. Notably, HHT/bortezomib lethality was dramatically reduced in BAK knockout or knockdown cells. Finally, HHT/bortezomib co-administration significantly improved survival compared to single agents in GC- and ABC- xenograft models while exhibiting little toxicity. These findings indicate that HHT and bortezomib cooperate to kill DLBCL and MCL cells through a process involving MCL-1 down-regulation, NOXA up-regulation, and BAK activation. They also suggest that a strategy combining HHT with bortezomib warrants attention in DLBCL and MCL. The online version of this article (10.1186/s12885-018-5018-x) contains supplementary material, which is available to authorized users.
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