Xiao Da-Kai, Du Yan-Zhi, Fan Hui-Yong, Chen Yu-Long, Chen Zhu, Zhang Ji, Wang Kan-Kan
Shanghai Institue of Hematology, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, China.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2005 Dec;13(6):975-8.
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 explore its mechanisms of effect on U937 cells. The cell growth and proliferation experiments were performed [corrected] cell apoptosis was detected by annexin V; reactive oxygen species (ROS) and mitochondrial transmembrane potential (DeltaPsim) were determined; protein [corrected] 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 markedly [corrected] induced apoptosis in U937 cells, triggered the generation of ROS, induced the loss of mitochondrial transmembrane potential, decreased the expression of procaspase-8 and procaspase-3. Pretreatment 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.
类视黄醇N-4-羟基苯基视黄酰胺（4-HPR，也称为非雷特韦）是全反式维甲酸（ATRA）的合成衍生物，在体外已显示出是一种有效的化学预防、化学治疗剂，并且是多种癌细胞类型（包括白血病细胞）中凋亡的有效诱导剂。然而，4-HPR产生凋亡效应的机制尚未完全阐明。本研究旨在研究4-HPR对几种白血病细胞的影响，并探讨其对U937细胞的作用机制。进行了细胞生长和增殖实验，通过膜联蛋白V检测细胞凋亡；测定活性氧（ROS）和线粒体跨膜电位（ΔΨm）；通过蛋白质印迹法检测蛋白质表达。结果表明，4-HPR以剂量和时间依赖性方式抑制U937细胞的增殖。4-HPR显著诱导U937细胞凋亡，触发ROS的产生，诱导线粒体跨膜电位的丧失，降低原半胱天冬酶-8和原半胱天冬酶-3的表达。L-抗坏血酸预处理可抑制ROS的产生、线粒体电位的破坏、半胱天冬酶的激活和细胞凋亡。结论是，ROS的产生随后线粒体跨膜电位的破坏在4-HPR诱导的白血病细胞凋亡中起重要作用，表明4-HPR可能是一种具有临床治疗癌症潜力的线粒体靶向药物。
