Benzodiazepine-induced superoxide signals B cell apoptosis: mechanistic insight and potential therapeutic utility.
Benzodiazepine-induced superoxide signals B cell apoptosis: mechanistic insight and potential therapeutic utility.
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苯二氮卓诱导的超氧化物信号 B 细胞凋亡：机制洞察和潜在的治疗效用。
DOI：
10.1172/jci16029
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Glick,GaryD
中科院分区：
文献类型：
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作者：
Blatt,NealB;Bednarski,JeffreyJ;Warner,RoscoeE;Leonetti,Francesco;Johnson,KathrynM;Boitano,Anthony;Yung,Raymond;Richardson,BruceC;Johnson,KentJ;Ellman,JonathanA;OpipariJr,AnthonyW;Glick,GaryD
描述了通过组合化学和表型筛选鉴定的促凋亡1，4-苯并二氮杂卓，Bz-423的性质。Bz-423在转化的拉莫斯B细胞中迅速产生超氧阴离子（O2-）。这种O2-响应起源于线粒体跨膜梯度崩溃和开放的渗透性转换孔之前的线粒体。Bz-423诱导的O2-起上游信号作用，启动以细胞色素释放、线粒体去极化和caspase激活为特征的凋亡程序。用阻断Bz-423诱导的O2-或O2-自由基形成的试剂预处理细胞减弱了死亡级联反应，这表明Bz-423的细胞杀伤依赖于O2-。拉莫斯细胞和生发中心B细胞之间的相似性促使实验确定Bz-423是否具有体内治疗活性。使用（NZ B × NZW）F1狼疮小鼠模型测试了这种可能性，在该模型中，病理性增强的生殖中心B细胞的存活和扩增介导疾病。Bz-423给药12周可特异性控制生发中心增生，并减少肾小球肾炎的组织学证据。总的来说，这些研究为苯二氮卓类药物定义了一种新的结构-功能关系，并指出了一种新的靶点和机制，这可能对开发治疗系统性红斑狼疮和相关疾病的改进药物具有价值。
The properties of a proapoptotic 1,4-benzodiazepine, Bz-423, identified through combinatorial chemistry and phenotype screening are described. Bz-423 rapidly generated superoxide (O2–) in transformed Ramos B cells. This O2–response originated from mitochondria prior to mitochondrial transmembrane gradient collapse and opening of the permeability transition pore. Bz-423–induced O2–functioned as an upstream signal that initiated an apoptotic program characterized by cytochromecrelease, mitochondrial depolarization, and caspase activation. Pretreatment of cells with agents that either block the formation of Bz-423–induced O2–or scavenge free radicals attenuated the death cascade, which demonstrated that cell killing by Bz-423 depends on O2–. Parallels between Ramos cells and germinal center B cells prompted experiments to determine whether Bz-423 had therapeutic activity in vivo. This possibility was tested using the (NZB × NZW)F1murine model of lupus, in which the pathologically enhanced survival and expansion of germinal center B cells mediate disease. Administration of Bz-423 for 12 weeks specifically controlled germinal center hyperplasia and reduced the histological evidence of glomerulonephritis. Collectively, these studies define a new structure-function relationship for benzodiazepines and point to a new target and mechanism that could be of value for developing improved drugs to manage systemic lupus erythematosus and related disorders.