Involvement of reactive oxygen species in N-(4-hydroxyphenyl)retinamide-induced apoptosis in cervical carcinoma cells
Involvement of reactive oxygen species in N-(4-hydroxyphenyl)retinamide-induced apoptosis in cervical carcinoma cells
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DOI：
10.1093/jnci/89.16.1191
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发表时间：
1997-08-20
期刊：
影响因子：
--
通讯作者：
Lotan, R
中科院分区：
文献类型：
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作者：
Oridate, N;Suzuki, S;Lotan, R
背景：N-(4-羟基苯基)维甲酰胺(4HPR)对肿瘤发生和生长的抑制作用可能是由于其诱导细胞凋亡(程序性细胞死亡)的能力所致，由于抗氧化剂抑制4HPR诱导的细胞凋亡，因此有计划进行实验以确定4HPR作用于凋亡细胞后，细胞内的活性氧水平是否增加。方法：用4HPR处理人宫颈癌细胞系C33A和正常宫颈上皮细胞，观察细胞存活、诱导细胞凋亡、产生活性氧以及细胞凋亡相关蛋白Bcl2和Bar的表达。结果：4HPR以时间和剂量依赖的方式诱导C33A细胞凋亡，3mU M或更高浓度的4HPR作用6~24小时，细胞出现典型的DNA片段化。0.4-10亩M4HPR处理1.5小时后，活性氧的产生增加了1.85倍至4.5倍。氧自由基清除剂吡咯烷二硫代氨基甲酸酯抑制细胞内活性氧的产生，抑制4HPR诱导的细胞凋亡，4HPR不能调节细胞内Bcl2和Bar蛋白的表达，4HPR的主要代谢产物N-(4-甲氧基苯基)维甲酰胺和其他几种与维甲酸受体或维甲酸X受体结合的维甲酸类化合物不能促进活性氧的产生，也不能诱导细胞凋亡。4与C33A宫颈癌细胞相比，HPR对正常人宫颈上皮细胞产生活性氧和诱导细胞凋亡的作用明显减弱。结论：4HPR诱导细胞凋亡可能与增强细胞内氧自由基的生成有关。[《癌症杂志》1997；89：1191-8]。
Background: The inhibitory effects of N-(4-hydroxyphenyl) retinamide (4HPR) on tumorigenesis and tumor growth may result from its ability to induce apoptosis (programmed cell death), Since antioxidants inhibit 4HPR-induced apoptosis, experiments were planned to determine whether the levels of reactive oxygen species increase in cells undergoing apoptosis after exposure to 4HPR. Methods: Cells of the human cervical carcinoma cell line C33A and normal human cervical epithelial cells were treated with 4HPR and analyzed for survival, induction of apoptosis, generation of reactive oxygen species, and expression of the apoptosis-related proteins Bcl-2 and Bar. Results: Treatment with 4HPR decreased C33A cell number by inducing apoptosis in a time-and dose-dependent fashion, DNA fragmentation typical of apoptosis was observed in cells exposed to 4HPR at concentrations of 3 mu M or higher for 6-24 hours. The generation of reactive oxygen species was enhanced by 1.85-fold to 4.5-fold after a 1.5-hour treatment with 0.4-10 mu M 4HPR. Pyrrolidine dithiocarbamate, an oxygen radical scavenger, suppressed the rate of generation of reactive oxygen species and inhibited 4HPR-induced apoptosis, 4HPR failed to modulate cellular levels of the Bcl-2 and Bar proteins, N-(4-Methoxyphenyl) retinamide, the major 4HPR metabolite, and several other retinoids that bind to nuclear retinoic acid receptors or retinoid X receptors failed to enhance the generation of reactive oxygen species and to induce apoptosis. 4HPR was much less effective in generating reactive oxygen species and in inducing apoptosis in normal human cervical epithelial cells than in C33A cervical carcinoma cells. Conclusions: Enhancement of the generation of reactive oxygen species may be involved in apoptotic pathway induction by 4HPR. [J Natl Cancer Inst 1997;89:1191-8].