Low dose of lenalidmide and PI3K/mTOR inhibitor trigger synergistic cytoxicity in activated B cell-like subtype of diffuse large B cell lymphoma.
Low dose of lenalidmide and PI3K/mTOR inhibitor trigger synergistic cytoxicity in activated B cell-like subtype of diffuse large B cell lymphoma.
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低剂量来那度胺和 PI3K/mTOR 抑制剂在弥漫性大 B 细胞淋巴瘤活化 B 细胞样亚型中引发协同细胞毒性
DOI：
10.1186/s13046-016-0327-x
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发表时间：
2016-03-24
期刊：
影响因子：
--
通讯作者：
Li J
中科院分区：
文献类型：
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作者：
Jin Z;Qing K;Ouyang Y;Liu Z;Wang W;Li X;Xu Z;Li J
背景活化B细胞样亚型弥漫性大B细胞淋巴瘤（ABC-DLBCL）临床表现为侵袭性强，预后差。针对关键通路可能会提高改善临床outcomes.MethodsThe协同效应进行了评估CCK-8测定和等效线图分析。通过流式细胞术、Western Blot和si-RNA转染测量NVP-Bez 235和来那度胺的细胞毒性。结果低剂量的两种药物均能显著抑制OCI-Ly 10裸鼠移植瘤的增殖，CI值< 1。NVP-Bez 235联合来那度胺可通过上调Bim、Bax和下调Bcl-xL的内源性途径增加细胞凋亡。Akt，尤其是NF-κB在协同作用中起重要作用。共处理还可诱导Su-DHL 2和OCI-Ly 3细胞周期阻滞于G 0/G1期，并通过增加p21表达、下调cyclinA和减少CDK 2磷酸化而减少S期，但在OCI-Ly 10中不存在。结论低剂量NVP-Bez 235联合来那度胺治疗ABC-DLBCL具有协同作用，其机制可能涉及细胞凋亡、Akt和NF-κB失活及细胞周期阻滞等多方面。共处理在体内也是有效的。这些数据为NVP-Bez 235和来那度胺的组合潜在治疗ABC-DLBCL铺平了道路。
BackgroundActivated B cell-like subtype of diffuse large B cell lymphoma (ABC-DLBCL) presents aggressive clinical courses and poor prognosis. Targeting key pathways may raise the possibility of improving clinical outcomes.MethodsThe synergetic effects were assessed by CCK-8 assay and measured by isobologram analysis. The NVP-Bez235 and lenalidomide cytotoxicity were measured by flow cytometry, Western Blot and si-RNA transfection. The combined treatment inducing tumor regression in vivo was performed in nude mice of OCI-Ly10 xenograft mouse model.ResultsLow dose of two agents represented significant inhibition of proliferation with CI value < 1. NVP-Bez235 combined with lenalidomide remarkably increased apoptosis through intrinsic pathway by upregulating Bim, Bax and downregulating Bcl-xL. Akt, especially NF-κB, played an important role in the synergetic effects. Cotreatment also induced the cell cycle to be arrested in G0/G1 phase, and decreased S phase by increasing p21 expression, downregulating cyclinA and diminishing CDK2 phosphorylation in Su-DHL2 and OCI-Ly3 but not in OCI-Ly10. Mice treated with NVP-Bez235/lenalidomide represented obvious tumor growth regression and prolonged overall survival.ConclusionsOur findings demonstrated the synergistic effect of low dose of NVP-Bez235 and lenalidomide in ABC-DLBCL, the underlying mechanism may be multifunctional, involving apoptosis, Akt and NF-κB inactivation and cell cycle arrest. Cotreatment was also effective in vivo. These data pave the way for potential treatment of ABC-DLBCL with combination of NVP-Bez235 and lenalidomide.