Jin Zhen, Qing Kai, Ouyang Yuan, Liu Zhao, Wang Wenfang, Li Xiaoyang, Xu Zizhen, Li Junmin
Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Hematology, Shanghai Institute of Hematology, Ruijin Hospital affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
J Exp Clin Cancer Res. 2016 Mar 24;35:52. doi: 10.1186/s13046-016-0327-x.
Activated 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.
The 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.
Low 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.
Our 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.
弥漫性大B细胞淋巴瘤活化B细胞样亚型（ABC-DLBCL）临床病程侵袭性强，预后较差。靶向关键信号通路可能提高改善临床结局的可能性。
采用CCK-8法评估协同效应，并通过等效线图分析进行测定。通过流式细胞术、蛋白质免疫印迹法和小干扰RNA转染检测NVP-Bez235和来那度胺的细胞毒性。在OCI-Ly10异种移植小鼠模型的裸鼠体内进行联合治疗诱导肿瘤消退。
低剂量的两种药物表现出显著的增殖抑制作用，联合指数（CI）值<1。NVP-Bez235与来那度胺联合使用通过上调Bim、Bax和下调Bcl-xL，显著增加了通过内源性途径的细胞凋亡。Akt，尤其是NF-κB，在协同效应中起重要作用。联合治疗还诱导细胞周期停滞在G0/G1期，并通过增加p21表达、下调细胞周期蛋白A和减少Su-DHL2和OCI-Ly3中CDK2的磷酸化来降低S期，但在OCI-Ly10中未出现这种情况。用NVP-Bez235/来那度胺治疗的小鼠表现出明显的肿瘤生长消退和总生存期延长。
我们的研究结果证明了低剂量的NVP-Bez235和来那度胺在ABC-DLBCL中的协同作用，其潜在机制可能是多方面的，涉及细胞凋亡、Akt和NF-κB失活以及细胞周期停滞。联合治疗在体内也有效。这些数据为NVP-Bez235和来那度胺联合治疗ABC-DLBCL的潜在应用铺平了道路。
