白血病细胞分化与凋亡的化学生物学研究  

Chemical biology study for differentiation and apoptosis of leukemic cell

作　　者：陈国强[1] 赵倩[1] 吴英理[1] 王立顺[1] 

机构地区：[1]上海交通大学医学院教育部细胞分化与凋亡重点实验室,上海200025

出　　处：《上海交通大学学报（医学版）》2012年第9期1145-1154,共10页Journal of Shanghai Jiao tong University:Medical Science

基　　金：国家重大科学研究计划项目(2009CB918404);国家自然科学基金重大研究计划(90813034);国家自然科学基金重点项目(30630034);国家自然科学基金面上项目(30870979;30870523;30871016;30973462;30971094;30971274;30971276;30971488;30971107;81070433;81071668;81070431;81172521;81171888;81170505;31100980;31170783);国家自然科学基金培育项目(91013008);科技部863计划(2008AA02Z301);上海市科委重点项目(08JC1413400;08JC1413500;08JC1413700)

摘　　要：近年来,以活性小分子化合物作为探针研究重要细胞生命活动规律为目的的化学生物学得到蓬勃发展,化学小分子探针日益成为生物医学研究的重要工具。本实验室以白血病细胞为模型,应用天然或合成的小分子化合物作为探针,在白血病细胞分化和凋亡的分子机制方面取得了系列发现。在白血病细胞分化方面的研究发现:天然小分子化合物腺花素可以诱导急性包括早幼粒白血病(APL)在内的多种急性粒细胞白血病(AML)细胞分化,减少白血病起始细胞(LIC)的数量,并显著延长APL白血病小鼠的生存时间。利用生物素标记的腺花素为探针,发现peroxiredoxin(PrxⅠ/Ⅱ)是腺花素的效应靶蛋白并揭示了腺花素和PrxⅠ/Ⅱ的作用模式,即腺花素以共价方式结合在PrxⅠ的cys173上并抑制其过氧化物酶活性,导致细胞内H2O2升高并活化ERK信号途径及上调C/EBPβ;揭示了白血病细胞诱导分化的一条新途径,也充分体现了化学与生物学结合的力量。相关研究还发现:一种天然小分子化合物pharicin B能够通过稳定RARα/PML-RARα蛋白,AML细胞系以及初发AML患者的原代细胞中增强全反式维甲酸(ATRA)诱导的细胞分化效应,并且能够恢复部分耐药的APL细胞对ATRA的敏感性。在白血病细胞凋亡方面的研究发现:纳摩尔浓度的喜树碱类衍生物NSC606985以时间-剂量依赖方式诱导AML细胞凋亡,并通过先后依次引起PKCδ蛋白剪切激活、线粒体跨膜电位崩塌和Caspase-3活化,从而诱导AML细胞发生凋亡;在此基础上进一步以NSC606985为探针,综合利用磷酸化修饰组学、定量蛋白质组学和亚细胞蛋白质组学的策略,对白血病细胞的凋亡进行系统性分析,绘制了NSC606985诱导白血病细胞凋亡的蛋白组学变化;以此为基础的研究发现,以ANP32B为代表的多个潜在的细胞凋亡分子,并对其中的NDRG1,ANP32B蛋白与细胞凋亡的关系进行了深入研究。更重�Chemical biology is a scientific interdiscipline spanning the fields of chemistry and biology that involves the application of chemical tools, often compounds, to the study and manipulation of biological systems. Remarkable achievements have been obtained on chemical biology which aims to study important biological events by using small molecular active compounds as a probe thus small active compound has become effective tools in the research of biomedicine. Our research group has achieved a series of results in the molecular mechanism study of leukemic cell differentiation and apoptosis through using small moleeular active compounds. We discovered that adenanthin, a diterpenoid compound extracted from Rabdosia adenantha, induces APL-like cell differentiation, represses tumor growth in vivo and prolongs the survival of mouse APL models that are sensitive and resistant to retinoic acid. The chemical probe biotin-tagged adenanthin was designed on the basis of structure-activity relationship data. Further study demonstrated adenanthin directly targets the conserved resolving eysteines of Prx I and Prx II and inhibits their peroxidase activities. Consequently, cellular H2O2 is elevated, leading to the activation of extracellular signal regulated kinases and increased transcription of C/EBPβ, which contributes to adenanthin-induced differentiation. In another study we identified a novel natural ent-kaurene diterpenoid derived from I. pharicus leaves called pharicin B that can rapidly stabilize RARα as well as PML-RARα protein and enhances ATRA-dependent transcriptional activity of RARα. Additionally, pharicin B enhances differentiation- enhancing effect of ATRA in AML cell lines, some primary leukemic cells and overcomes retinoid resistance in ATRA-resistant subclones. The effectiveness of the ATRA/pharicin B combination warrants further investigation on their use as a therapeutic strategy for AML patients. Based on our previous study that NSC606985, a novel camptothecin analog, could effectively induce apoptosis

关 键 词：化学生物学 白血病 细胞分化 细胞凋亡 

分 类 号：R733.7[医药卫生—肿瘤]