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西南医科大学附属医院皮肤科,泸州,646000
纸质出版日期:2023,
网络出版日期:2023-9-20,
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王佳女, 刘利, 熊霞, 等. 新型小分子抑制剂15 h通过靶向BRD4诱导弥漫性大B细胞淋巴瘤细胞凋亡[J]. 西南医科大学学报, 2023,46(5):413-417.
WANG Jianv, LIU Li, XIONG Xia, et al. Novel small molecule inhibitor 15h induces cell apoptosis in diffuse large B-cell lymphoma cells by targeting BRD4[J]. Journal of Southwest Medical University, 2023,46(5):413-417.
王佳女, 刘利, 熊霞, 等. 新型小分子抑制剂15 h通过靶向BRD4诱导弥漫性大B细胞淋巴瘤细胞凋亡[J]. 西南医科大学学报, 2023,46(5):413-417. DOI: 10.3969/j.issn.2096-3351.2023.05.009.
WANG Jianv, LIU Li, XIONG Xia, et al. Novel small molecule inhibitor 15h induces cell apoptosis in diffuse large B-cell lymphoma cells by targeting BRD4[J]. Journal of Southwest Medical University, 2023,46(5):413-417. DOI: 10.3969/j.issn.2096-3351.2023.05.009.
目的研究一种靶向溴结构域蛋白4(bromodomain-containing protein 4,BRD4)的新型小分子抑制剂15h(简称15h)对弥漫性大B 细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)细胞凋亡的影响并探索其作用机制。方法首先运用Alphascreen 实验探索15h 对BET 主要家族成员的靶向抑制作用、MTT 法检测15h 对几种血液系统恶性肿瘤细胞株细胞活力的影响。其次采用流式细胞术检测15h 对DL BCL 细胞凋亡的影响。最后利用Western blot 和qRT-PCR 分析15h 对凋亡相关蛋白Bcl-2、Bax 和转录因子C-Myc 的调控作用。结果15h 主要靶向抑制BET 蛋白家族成员BRD4,对OCI-LY10 细胞活力的抑制作用呈现时间和浓度依赖性。与对照组相比,细胞凋亡率从(4.612 ± 0.13)%逐渐增加到(50.7 ± 4.35)%。Western blot 和qRT-PCR 检测结果表明经15h 处理后的OCI-LY10 细胞,其转录因子C-Myc 表达被抑制,促凋亡蛋白Bax 上调、抗凋亡蛋白Bcl-2 下调。结论新型小分子抑制剂15h 可能通过靶向抑制BRD4 与转录因子C-Myc 的结合,抑制C-Myc 基因转录,进而上调Bax、下调Bcl-2,最终诱导DLBCL 细胞凋亡。
Objective The objective of this study was to investigate the impact of a novel small molecule inhibitor,15h,target⁃ ing bromodomain-containing protein 4 (BRD4),on apoptosis in diffuse large B-cell lymphoma (DLBCL) cells and explore its prelimi⁃ nary mechanism of action. Methods Firstly,the Alphascreen assay was used to explore the targeted inhibitory effect of 15h on BET family members,and the effect of 15h on cell viability in various hematologic malignancy cell lines was assessed using the MTT method. Flow cytometry was employed to examine the effect of 15h on DLBCL cell apoptosis. Finally,Western blot and qRT-PCR analyses were conducted to evaluate the regulatory effects of 15h on apoptosis-related proteins,including Bcl-2,Bax,and transcrip⁃ tion factor C-Myc. Results 15h primarily targeted and inhibited the BET protein family member BRD4,exhibiting a time- and concentration-dependent inhibitory effect on OCI-LY10 cell viability. Compared to the control group,the apoptotic rate gradually in⁃ creased from (4.612 ± 0.13)% to (50.7 ± 4.35)% (P < 0.05). Western blot and qRT-PCR analyses demonstrated that 15h treatment sup⁃ pressed the expression of the transcription factor C-Myc while up-regulating the pro-apoptotic protein Bax and down-regulating the anti-apoptotic protein Bcl-2 in OCI-LY10 cells. Conclusion The novel small-molecule inhibitor,15h,might exert its effects by tar⁃ geting the binding of BRD4 to the transcription factor C-Myc,thereby inhibiting C-Myc gene transcription and ultimately inducing apoptosis in DLBCL cells.
弥漫性大B 细胞淋巴瘤BRD4c-Myc细胞凋亡
Diffuse large B-cell lymphoma (DLBCL)BRD4c-MycCell apoptosis
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