BACKGROUND Bcl-2 family members play an important role in the development of malignant lymphoma and can induce drug resistance in anticancer treatment. The development of small molecules targeting Bcl-2 family proteins may be a new strategy for the treatment of malignant lymphoma. In this study, we investigate the antitumor effect and cellular mechanism of a novel Bcl-2/Bcl-xL dual inhibitor, BM-1197, in DCBCL and Burkitt lymphoma cells. METHODS The CCK-8 assay was used to detect cell viability. Apoptosis was determined by Hoechst 33258 staining and flow cytometry. The activity of caspase-3/caspase-9 was determined using a caspase-3/caspase-9 activity kit. Western blotting analysis was performed to evaluate the changes in protein expression. Functional analysis was performed via immunoprecipitation and siRNA interference. Human malignant lymphoma xenograft models in nude mice were established for in vivo efficacy detection. RESULTS We find that BM-1197 exerts potent growth-inhibitory activity against lymphoma cells that harbor high expression of Bcl-2 and Bcl-xL in vitro and has a synergistic effect with chemotherapeutic drugs. Mechanistically, we see that the intrinsic apoptosis pathway is activated upon BM-1197 treatment. BM-1197 affects the protein interactions of Bak/Bcl-xl, Bim/Bcl-2, Bim/Bcl-xl, and PUMA/Bcl-2 and induces conformational changes in the Bax protein, which result in the activation of Bax and release of cytochrome c, activate caspase - 9, - 3, and - 7 and finally induce cell apoptosis. Furthermore, our data demonstrate that BM-1197 exhibits strong anti-tumor effects against established human malignant lymphoma xenograft models. CONCLUSIONS Our study demonstrated BM-1197 exerts potent antitumor effects both in vitro and in vivo and provides promising preclinical data for the further development of BM-1197 in malignant lymphoma.

中文翻译：

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新型Bcl-2抑制剂BM-1197通过内源性凋亡途径诱导恶性淋巴瘤细胞凋亡。

背景Bcl-2家族成员在恶性淋巴瘤的发生中起重要作用，并可以在抗癌治疗中诱导耐药性。靶向Bcl-2家族蛋白的小分子的发展可能是治疗恶性淋巴瘤的新策略。在这项研究中，我们研究了新型Bcl-2 / Bcl-xL双重抑制剂BM-1197在DCBCL和Burkitt淋巴瘤细胞中的抗肿瘤作用和细胞机制。方法采用CCK-8法检测细胞活力。通过Hoechst 33258染色和流式细胞术确定细胞凋亡。使用caspase-3 / caspase-9活性试剂盒确定caspase-3 / caspase-9的活性。进行蛋白质印迹分析以评估蛋白质表达的变化。通过免疫沉淀和siRNA干扰进行功能分析。建立裸鼠的人恶性淋巴瘤异种移植模型以用于体内功效检测。结果我们发现BM-1197对淋巴瘤细胞具有强大的生长抑制活性，该淋巴瘤细胞在体外具有高表达的Bcl-2和Bcl-xL，并且与化疗药物具有协同作用。从机理上讲，我们看到固有的凋亡途径在BM-1197处理后被激活。BM-1197影响Bak / Bcl-xl，Bim / Bcl-2，Bim / Bcl-xl和PUMA / Bcl-2的蛋白质相互作用，并诱导Bax蛋白质发生构象变化，从而导致Bax活化和释放细胞色素c的活化，激活caspase-9，-3和-7并最终诱导细胞凋亡。此外，我们的数据表明BM-1197对已建立的人类恶性淋巴瘤异种移植模型表现出强大的抗肿瘤作用。