目的： 探讨γ-分泌酶抑制剂（gamma-secretase inhibitor，GSI）对伯基特淋巴瘤（Burkitt lymphoma，BL）Namalwa细胞增殖与凋亡的影响及其可能的作用机制。方法： GSI处理Namalwa细胞后，MTT法检测细胞增殖抑制率，流式细胞术检测细胞的凋亡，Western blotting法检测凋亡相关蛋白caspase-9、caspase-3以及Notch信号通路中Notch1蛋白胞内片段的表达。建立裸鼠移植瘤模型，观察GSI对裸鼠移植瘤生长的抑制作用。结果： GSI处理Namalwa细胞48、72 h的 IC50值分别为2.14和0.61 μmol/L，GSI对Namalwa细胞的增殖抑制作用呈剂量和时间依赖性。GSI（1.25 μmol/L）处理Namalwa细胞24 h后，其凋亡率明显高于对照组\[（17.71±1.87）% vs （3.42±0.95）%，P<0.01\]；处理48 h后与对照组差异更为显著\[（43.68±053）% vs （4.65±0.8）%，P<0.01\]。GSI处理Namalwa细胞24、48 h后，凋亡蛋白caspase-3、caspase-9蛋白前体表达下降，caspase-9活性片段表达上调，Notch1蛋白胞內片段表达下降。GSI处理后裸鼠移植瘤体积明显小于对照组 \[13 d时，（2.199±0.183） vs （ 1.15±0.399）cm3，P<0.01]；瘤组织中Namalwa细胞的凋亡率明显高于对照组\[（5.3±0.48）% vs （2.1±0.26）%，P<0.01\]。结论： GSI能够有效抑制BL细胞株Namalwa细胞的增殖及促进其凋亡，caspase-3和caspese-9凋亡蛋白以及Notch信号通路可能参与GSI诱导Namalwa细胞凋亡的过程。

Objective: To investigate the effect of γ-secretase inhibitor (GSI) on proliferation and apoptosis of B lymphoma in vitro and in vivo. Methods: In experiments in vitro, Burkitt lymphoma (BL) Namalwa cells were treated with GSI at different concentrations. At different time points after treatment, cell viability and apoptosis were assessed by MTT assay and flow cytometry, respectively. Apoptosis-related proteins caspase-3 and caspase-9 and Notch signaling pathway proteins were assessed by Western blotting. In experiments in vivo, nude mice were injected with Namalwa cells. Mice that developed tumor lesions after xenograft implantation were treated with GSI or PBS. Tumor development was comparatively assessed in the two treatment groups. Results: GSI inhibited Namalwa cell proliferation in time- and dose-dependent manners; at 48 h and 72 h after treatment, the IC50 value was 2.14 μmol/L and 0.61 μmol/L, respectively. GSI also induced Namalwa cell apoptosis in a time-dependent manner; (17.71±1.87)% of Namalwa cells treated with GSI at 125 μmol/L but only 3.42±0.95 % of cells treated with PBS underwent apoptosis at 24 h (P<0.01), and these numbers (43.68±0.53)% and (4.65±0.8)%, respectively, at 48 (P<0.01). Contents of caspase-3 and caspase-9 and intracellular Notch proteins were decreased but activated caspase-9 protein content was increased in a time-dependent manner in Namalwa cells after GSI treatment. In tumor-bearing nude mice, GSI treatment for 13 days resulted in a significant decrease in the tumor volume as compared with the PBS control (2.199±0.183% vs 1.15±0.399%, P＜0.01). Correspondingly, a significantly higher rate of apoptosis was detected in tumors from GSI-treated animals (5.3±0.48)% than in PBS-treated animals (2.1±0.26) %(P<0.01). Conclusions: GSI can efficiently inhibit the proliferation and promote apoptosis of B lymphoma cells, at least through regulating caspase-3 and caspase-9 and Notch signaling pathway.

国家青年科学基金资助项目（No. 81101786）；江苏省“六大人才高峰”资助项目（No. 2011-ws-062）。