Fenretinide诱导白血病细胞凋亡的机理研究  

Mechanisms of Fenretinide-Triggered Apoptosis in Leukemic Cells

作　　者：肖大凯[1] 杜艳芝[1] 范惠咏[1] 陈玉龙[1] 陈竺[1] 张济[1] 王侃侃[1] 

机构地区：[1]上海第二医科大学附属瑞金医院,上海血液学研究所上海200025

出　　处：《中国实验血液学杂志》2005年第6期975-978,共4页Journal of Experimental Hematology

基　　金：国家自然科学基金(编号30328028和30300409);上海市科委启明星计划(04QMIX1427)资助

摘　　要：Fenretinide(4HPR)是人工合成的全反式维甲酸衍生物,能够通过诱导凋亡抑制多种肿瘤细胞生长和增殖,但是其机理尚不很清楚。本研究考察4HPR对几种白血病细胞的影响,并用U937为对象研究其作用机制。在研究中进行了细胞生长和增殖实验,以膜联蛋白检测细胞凋亡,测定活性氧(ROS)和线粒体跨膜电位(ΔΨm)及用Westernblot检测蛋白表达。研究结果表明,4-HPR能够剂量依赖性地抑制多种白血病细胞株的增殖,进一步发现4HPR能够诱导U937细胞发生凋亡,并且此凋亡可以被维生素C所抑制.此凋亡过程伴有活性氧的升高,线粒体跨膜电位的下降,以及酶原型胱冬酶8(caspase8),3的蛋白水平表达下降。结论:4HPR可能通过升高细胞内ROS的水平,造成线粒体膜损伤,引发由caspase家族成员介导的凋亡,提示4HPR可能是一种线粒体靶向的药物。The retinoid N-4-hydroxyphenyl retinamide （4-HPR also known as fenretinide） , a synthetic derivative of all trans retinoic acid（ATRA） , has shown as an efficient chemopreventive, chemotherapeutic agent and a potent inducer of apoptosis in various cancer cell types in vitro, including leukemic cells. However the mechanisms by which 4-HPR has the apoptotic effects is not completely elucidated. This study was aimed to investigate the effect of 4-HPR on several leukemic cells and explone its mechanisms of effect on U937 cells. The cell growth and proliferation experiments were perfamed; cell apoptosis was detected by annexin V; reactive oxygen species （ROS） and mitochrondial transmembrane potential （△Ψm） were determined; protlein expression was detected by Western blot. The results showed that 4-HPR inhibited the proliferation of U937 cells in a dose- and time-dependent manner. 4-HPR markly induced apoptosis in U937 cells, triggeret the generation of ROS, induced the loss of mitochondrial transmembrane potential, decreased the expression of procaspase-8 and procaspase-3. Pretreament of L-ascorbic acid suppressed the generation of ROS, disruption of mitochondrial potential, activation of caspases and apoptosis. It is concluded that the generation of ROS followed by the disruption of mitochondrial transmembrane potential plays an important role on 4-HPR-induced apoptosis in leukemic cells, suggesting that 4-HPR may be one of mitochondrial-targeted agents with clinical potential in treating cancer.

关 键 词：FENRETINIDE 白血病 细胞凋亡 活性氧 胱冬酶 

分 类 号：R733.7[医药卫生—肿瘤] R977.2[医药卫生—临床医学]