天然产物研究与开发 ›› 2023, Vol. 35 ›› Issue (增刊2): 93-98.

• 开发研究 • 上一篇    下一篇

白藜芦醇靶向BCL6抑制弥漫大B细胞淋巴瘤生长研究

邢雅婧1,2,罗晓玲1,刘周江1,文兴建1,刘晏齐1,钟亚东1,2,3*   

  1. 1重庆市中药研究院,重庆 400065;2重庆中医药学院,重庆 402760;3重庆医科大学公共卫生学院,重庆401331
  • 出版日期:2023-12-28 发布日期:2023-12-11
  • 基金资助:
    重庆市中药研究院基本科研业务费项目(jbky2020 0006);中国博士后科学基金面上项目(2022MD 713703),重庆市自然科学基金博士后科学基金项目(cstc2021jcyj-bshX0009)

Effect of resveratrol on inhibiting the growth of diffuse large B cell lymphoma by targeting BCL6

XING Ya-jing1,2,LUO Xiao-ling1,LIU Zhou-jiang1,WEN Xing-jian1,LIU Yan-qi1,ZHONG Ya-dong1,2,3*   

  1. 1Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China;2Chongqing College of Traditional Chinese Medicine, Chongqing 402760,China;3College of Public Health, Chongqing Medical University, Chongqing 401331, China
  • Online:2023-12-28 Published:2023-12-11

摘要:

研究白藜芦醇通过抑制B细胞淋巴瘤因子6(B cell lymphoma 6,BCL6)活性从而抑制弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)生长的功能。采用分子对接实验预测白藜芦醇与BCL6的结合位点,双荧光素酶报告系统检测白藜芦醇对BCL6转录活性的抑制作用,实时荧光定量PCR检测白藜芦醇对BCL6下游靶基因p53、ATR、CDKN1A、CD69和CXCR4的上调效果,MTS法检测白藜芦醇体外对DLBCL增殖的抑制作用,SCID小鼠异种移植模型探究白藜芦醇体内对DLBCL的抑制效果。结果显示,白藜芦醇可以与BCL6的Met51、Ala52和Val117号氨基酸残基形成稳定的氢键,与BCL6蛋白结合。双荧光素酶报告实验证明白藜芦醇可以抑制BCL6的转录抑制活性,qPCR实验进一步验证白藜芦醇可以激活BCL6下游靶基因的表达,并呈浓度依赖性。MTS实验证明白藜芦醇可以在体外抑制DLBCL的增殖,SCID小鼠异种移植模型证明白藜芦醇在体内抑制DLBCL生长。综上结果,白藜芦醇可以通过抑制BCL6活性进而抑制DLBCL的生长,有望成为治疗DLBCL的候选药物。

关键词: 白藜芦醇, 弥漫大B细胞淋巴瘤, BCL6, 肿瘤生长

Abstract:

To investigate the function of resveratrol on inhibiting the growth of diffuse large B cell lymphoma (DLBCL) by inhibiting the activity of B cell lymphoma factor 6 (BCL6).Molecular docking experiment was used to predict the binding sites of resveratrol with BCL6.The inhibitory effect of resveratrol on the transcriptional activity of BCL6 was detected by dual luciferase reporter system.To detect the up-regulation effect of resveratrol on BCL6 downstream target genes p53,ATR,CDKN1A,CD69 and CXCR4,we conducted real-time quantitative PCR assay.The inhibitory effect of resveratrol on proliferation of DLBCL was detected by MTS assay in vitro and SCID mouse xenograft models in vivo.The results showed that resveratrol could form stable hydrogen bonds with residues of Met51,Ala52 and Val117 of BCL6,and bind to BCL6 protein.Double luciferase assay demonstrated that resveratrol inhibited the transcriptional inhibitory activity of BCL6.qPCR assay further confirmed that resveratrol could reactivate the expression of BCL6 target genes in a concentration-dependent manner.MTS assay demonstrated that resveratrol could inhibit DLBCL cells growth in vitro and SCID mouse xenograft models demonstrated that resveratrol inhibited the growth of DLBCL in vivo.In conclusion,resveratrol inhibits the growth of DLBCL by inhibiting the activity of BCL6,which is expected to be a candidate drug for the treatment of DLBCL.

Key words: resveratrol, diffuse large B cell lymphoma, BCL6, tumor growth

中图分类号:  R966