Division of Hematology/Oncology, Virginia Commonwealth University Richmond, Room 229 Goodwin Research Building, 401 College Street, Richmond, VA, 23229, USA.
Massey Cancer Center, Virginia Commonwealth University Richmond, Richmond, VA, USA.
BMC Cancer. 2018 Nov 16;18(1):1129. doi: 10.1186/s12885-018-5018-x.
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.
本研究旨在探讨蛋白合成抑制剂高三尖杉酯碱（HHT）与蛋白酶体抑制剂硼替佐米在弥漫性大 B 细胞淋巴瘤（DLBCL）和套细胞淋巴瘤（MCL）细胞中的相互作用。
将各种 DLBCL 和 MCL 细胞分别单独或联合暴露于 HHT 和硼替佐米后，通过流式细胞术和 Western blot 分析监测细胞凋亡和信号通路的改变。利用异种移植小鼠模型评估肿瘤生长和动物存活情况。
HHT 和硼替佐米联合用药可协同诱导 GC-、ABC-和双打击 DLBCL 细胞发生凋亡。在 MCL 细胞和原发性淋巴瘤细胞中也观察到类似的相互作用。HHT/硼替佐米联合用药可减少 MCL-1 与 BAK 和 NOXA 的结合。敲低 NOXA 可显著降低细胞致死率，而敲低 MCL-1 或过表达 NOXA 则会增加细胞死亡。值得注意的是，BAK 敲除或敲低细胞可显著降低 HHT/硼替佐米的致死率。最后，与单药治疗相比，HHT/硼替佐米联合用药可显著提高 GC-和 ABC-异种移植模型的存活率，而毒性较小。
这些发现表明，HHT 和硼替佐米通过下调 MCL-1、上调 NOXA 和激活 BAK 来协同杀伤 DLBCL 和 MCL 细胞。这些发现还提示，联合应用 HHT 和硼替佐米的策略值得关注，可用于治疗 DLBCL 和 MCL。
