选择性白介素-2受体抑制剂TPD7抗白血病作用及机制研究
结题报告
批准号:
81603148
项目类别:
青年科学基金项目
资助金额:
17.3 万元
负责人:
马维娜
依托单位:
学科分类:
H3505.抗肿瘤药物药理
结题年份:
2019
批准年份:
2016
项目状态:
已结题
项目参与者:
潘晓艳、黄静、林园园、马玉娇、李灵芝、朱曼
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中文摘要
白血病是造血干细胞的恶性肿瘤,该病在儿科恶性肿瘤的发病率中居首位。分子靶向抑制剂研究是高效抗肿瘤药物研发的重要途径。白介素2受体(IL-2R)在细胞因子网络调节中起关键作用。IL-2R及其下游信号分子缺陷可能是肿瘤免疫逃逸的重要原因,纠正这种缺陷可用于肿瘤治疗。IL-2R分为三个亚基,分别为α、β和γ链,各自介导不同的信号通路从而影响生命活动。因此同时阻断IL-2Rα、β和γ通路是肿瘤治疗的一种新思路。在前期研究工作中,应用细胞膜色谱(CMC)技术从天然产物塔斯品碱的系列衍生物中筛选发现了全新结构的具有抗肿瘤活性的衍生物TPD7。本课题将在体内和体外研究TPD7抗白血病作用及其机制,通过建立电化学技术与CMC模型研究TPD7与IL-2R的相互作用,在分子水平上研究TPD7对IL-2R信号通路的抑制作用,并通过尾静脉注射方式研究TPD7的体内抑瘤作用,为开发高效抗白血病药物奠定实验基础。
英文摘要
Leukemia is a malignant tumour of the hematopoietic stem cells, statistics found that the incidence of the disease in pediatric malignant tumors is in the first place. One of the important ways for antitumor innovative drug research is to look for molecular targeted inhibitors. Interleukin 2 receptor (IL-2R) plays a key role in regulation of cytokine network. The defects of IL-2R and its downstream signaling molecules may be important reasons of tumor immune escape, thus correcting the defects can be used in tumor therapy. IL-2R is divided into three subunits, alpha, beta, and gamma chain, respectively. Each subunit mediates different signaling pathways, and affects life activities together. Using a combination of IL-2Rα, IL-2Rβ and IL-2Rγ inhibitors to completely block the IL-2R pathway is a very potent therapy in tumor therapy. In the previous studies, with cell membrane chromatography we found that the taspine derivative TPD7 could against tumor. In this study, in vitro and in vivo experiments were used to study the effect and mechanism for TPD7 against leukemia. The electrochemical techniques and cell membrane chromatography method were established to determine whether TPD7 competitively inhibits binding of IL-2 to the IL-2R, and the underlying mechanism for TPD7 inhibition of leukemia growth was investigated. We further characterized the anticancer effects of TPD7 in vivo by tail vein injections. The aim of this study is to establish the foundation for finding the novel compound with effective anti- leukemia activity.
IL-2R信号通路是免疫细胞增殖和分化的关键调控因子,已成为肿瘤治疗的潜在药物靶点。然而其相关肿瘤抑制剂的研究甚少。TPD7是一种新型的具有抗癌作用的联苯脲塔斯品碱衍生物。本研究确证了TPD7对T细胞淋巴瘤的抗肿瘤活性,并探讨了其靶向IL-2R信号通路的潜在作用机制。研究结果表明,TPD7对肿瘤细胞增殖具有显著的抑制作用,且其与IL-2R的表达水平呈现较强的相关性,其中T细胞淋巴瘤H9和HUT78细胞对TPD7最为敏感。同时,TPD7与IL-2R结合良好,下调IL-2R的mRNA和蛋白表达水平。此外,TPD7调控IL-2R下游信号通路包括JAK/STAT, PI3K/AKT/mTOR和PLCγ/Raf/MAPK,从而调控Bcl-2线粒体凋亡通路和细胞周期蛋白CDK/Cyclins。研究结果表明,TPD7通过线粒体途径促进H9细胞凋亡,并阻碍细胞周期于G2/M期。因此,TPD7通过调节IL-2R信号通路来治疗T细胞淋巴瘤,成为治疗T细胞淋巴瘤的潜在候选药物。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL-2R signalling pathway
TPD7通过调节IL-2R信号通路抑制皮肤T细胞淋巴瘤H9细胞生长
DOI:10.1111/jcmm.14810
发表时间:2019
期刊:Journal of Cellular and Molecular Medicine
影响因子:5.3
作者:Zhu Man;Yang Liu;Shi Xianpeng;Gong Zhengyan;Yu Runze;Zhang Dongdong;Zhang Yanmin;Ma Weina
通讯作者:Ma Weina
Synergistic Effect of TPD7 and Berberine against Leukemia Jurkat Cell Growth through Regulating Ephrin-B2 Signaling
TPD7 和小檗碱通过调节 Ephrin-B2 信号传导对白血病 Jurkat 细胞生长的协同作用
DOI:10.1002/ptr.5866
发表时间:2017-09-01
期刊:PHYTOTHERAPY RESEARCH
影响因子:7.2
作者:Ma, Weina;Zhu, Man;Zhang, Yanmin
通讯作者:Zhang, Yanmin
Interaction of Taspine Derivative TPD7 with Vascular Endothelial Growth Factor Receptor 2 by Cell Membrane Chromatography
通过细胞膜色谱法研究 Taspine 衍生物 TPD7 与血管内皮生长因子受体 2 的相互作用
DOI:10.1007/s10337-019-03801-1
发表时间:2019-12-01
期刊:CHROMATOGRAPHIA
影响因子:1.7
作者:Yang,Liu;Zeng,Yingnan;Ma,Weina
通讯作者:Ma,Weina
Ephrin type-B receptor 4 affinity chromatography: An effective and rapid method studying the active compounds targeting Ephrin type-B receptor 4
Ephrin B 型受体 4 亲和色谱:研究靶向 Ephrin B 型受体 4 的活性化合物的有效且快速的方法
DOI:10.1016/j.chroma.2018.12.005
发表时间:2019-02-08
期刊:JOURNAL OF CHROMATOGRAPHY A
影响因子:4.1
作者:Zhu, Man;Cui, Yuxin;Zhang, Yanmin
通讯作者:Zhang, Yanmin
DOI:10.1002/jmr.2701
发表时间:2018-06-01
期刊:JOURNAL OF MOLECULAR RECOGNITION
影响因子:2.7
作者:Yang, Liu;Zhu, Man;Ma, Weina
通讯作者:Ma, Weina
国内基金
海外基金