The γ-secretase inhibitor GSI-I interacts synergistically with the proteasome inhibitor bortezomib to induce ALK plus anaplastic large cell lymphoma cell apoptosis
The γ-secretase inhibitor GSI-I interacts synergistically with the proteasome inhibitor bortezomib to induce ALK plus anaplastic large cell lymphoma cell apoptosis
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γ-分泌酶抑制剂 GSI-I 与蛋白酶体抑制剂硼替佐米协同相互作用诱导 ALK 加间变性大细胞淋巴瘤细胞凋亡
DOI：
10.1016/j.cellsig.2019.03.013
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发表时间：
2019-07-01
影响因子：
4.8
通讯作者：
Shi, Wenyu
中科院分区：
文献类型：
--
作者：
Dang, Qingxiu;Chen, Lili;Shi, Wenyu
γ-分泌酶抑制剂 (GSI-I) 或蛋白酶体抑制剂单药治疗间变性淋巴瘤激酶阳性间变性大细胞淋巴瘤 (ALK + ALCL) 显示有限的反应和相当大的毒性。在这里，我们在体内和体外检查了低剂量 GSI-I 和蛋白酶体抑制剂硼替佐米 (BTZ) 组合对 ALK + ALCL 细胞的影响。我们发现，与单独使用 BTZ 或 GSI-I 相比，用 BTZ 和 GSI-I 联合治疗处理的 ALK + ALCL 细胞显示出细胞凋亡增加，这与 caspase 激活增加一致。联合治疗还抑制 AKT 和细胞外信号相关激酶途径，以及应激相关级联，包括 c-jun N 末端激酶和应激激活激酶。此外，小鼠异种移植模型中的联合治疗导致肿瘤组织细胞凋亡增加并减少肿瘤生长。我们的结果揭示了低剂量的γ-分泌酶抑制剂和蛋白酶体抑制剂的协同抗肿瘤作用，并表明可耐受的 BTZ/GSI-I 联合药物在未来临床治疗中治疗 ALK + ALCL 的潜在应用。
Single agent treatment of the gamma-secretase inhibitor (GSI-I) or proteasome inhibitor in anaplastic lymphoma kinase positive anaplastic large cell lymphoma (ALK + ALCL) shows limited response and considerable toxicity. Here, we examined the effects of the combination of low dose GSI-I and the proteasome inhibitor bortezomib (BTZ) in ALK + ALCL cells in vivo and in vitro. We found that ALK + ALCL cells treated with the BTZ and GSI-I combination treatment showed elevated apoptosis, consistent with increased caspase activation, compared with BTZ or GSI-I alone. The combination treatment also inhibited AKT and extracellular signal-related kinase pathways, as well as stress-related cascades, including the c-jun N-terminal kinase and stress-activated kinases. Moreover, combined treatment in a murine xenograft model resulted in increased apoptosis in tumor tissues and reduced tumor growth. Our results reveal the synergistic anti-tumor effects of low dose inhibitors against gamma-secretase and the proteasome and suggest the potential application of the tolerable BTZ/GSI-I combined agents in treating ALK + ALCL in future clinical treatment.