有机硅季铵盐联合5-FU对肝癌细胞增殖及凋亡的影响
摘要
目的：原发性肝癌的治疗目前仍然存在一些困难,手术切除过程中种植转移难免发生,解决手术中种植转移问题势在必行,本研究使用有机硅季铵盐、5-FU及两药联合作用于体外肝癌细胞(SMMC-7721人肝癌细胞,R15大鼠肝癌细胞)的实验方法,探讨有机硅季铵盐(洁悠神)单独及联合5-FU对肝癌细胞的作用及机制,为临床肝癌的治疗及预防术中转移提供新的药物及思路。
方法：在本研究中,体外培养SMMC-7721人肝癌细胞,R15大鼠肝癌细胞,使用不同浓度的有机硅季铵盐、不同浓度的5-FU及两药联合处理细胞,应用细胞形态观察、MTT比色法、Hochest染色、透射电镜、细胞周期、流式细胞术(Flow CytoMeter,FCM)和Western免疫印迹(Western blotting)等方法,研究洁悠神、5-FU及两药联合对肝癌细胞的作用。
结果：用不同浓度的药物处理两种肝癌细胞不同时间,细胞形态学观察肿瘤细胞表现为脱壁、变小和皱缩等凋亡现象；透射电镜观察发现细胞出现凋亡小体,MTT比色试验结果表明有机硅季铵盐对SMMC-7721人肝癌细胞,R15大鼠肝癌细胞的增殖活性有明显的抑制作用；FCM结果显示SMMC-7721人肝癌细胞,R15大鼠肝癌细胞在药物处理后凋亡细胞数明显增加,并且对抑制肿瘤细胞增殖作用及诱导肿瘤细胞凋亡作用随着药物作用时间和药物浓度的增加随之增加；Western blotting结果表明Bax、Caspase3、 Caspase8蛋白表达增加,而Bcl-2蛋白表达降低。
结论：有机硅季铵盐可能是一个有效的抗肿瘤药物；有机硅季铵盐联合5-FU表现出协同抑制效果;联合用药的作用机制为抑制细胞周期,诱导细胞凋亡,激活凋亡蛋白caspases-3、caspases-8和caspases-9,并下调bcl-2的表达,通过影响线粒体凋亡途径的基因表达,促进肿瘤细胞凋亡以达到抗肿瘤的效果；本研究将为抗肿瘤药物的研发提供新思路。
Purpose:There are still some difficulties we faced in the clinical treatment of HCC. The implantation metastasis in liver cancer operation is an urgent problem needed to be solved. In this study, we have investigated the effects of individual and joint action of organic silicone quaternary ammonium salt (Jieyoushen) and5-fluorouracil (5-FU) in human hepatocellular carcinoma SMMC7721cells lines and R15cell lines of rat in vitro. Here we assessed the characteristics of the drugs to explore the effects of individual and joint action of Jieyoushen and5-FU.
Methods:MTT assay was used to investigate the inhibitory effects of these agents. Electron microscopy and Hoechst33342staining were used to observe the morphological changes of liver cell lines treated with Jieyoushen and5-FU. Flow cytometry were performed to detect the cycle and apoptosis of liver cell lines with Jieyoushen and5-FU. The expression of caspases-3and8, bax, bcl-2, and survivin protein in these cells were determined by western blotting.
Results:The results of MTT assays showed that single and joint action Jieyoushen and5-FU inhibited the proliferation of liver carcinoma cell lines in a dose-and time-dependent manner respectively. And electron microscopy and Hoechst33342staining showed that characteristic apoptotic bodies were visible in apoptotic cell treated with Jieyoushen and5-FU. Flow cytometry results indicated that the percentages of cells at G0/G1phase gradually increased, while gradually decreased during S phase after the treatment. The medication leds to the changes on expression of proteins caspases-3,-8, bax, bcl-2and survivin. Compared with the control group, the expression levels of bax, caspase-8and caspase-3protein increased significantly in the SMMC7721and R15cells after24hours treatment, meanwhile, the bcl-2protein expression decreased significantly.
Conclusions:It can be concluded that the combination of Jieyoushen with5-FU showed a better inhibitory effect than either agent alone. The mechanism of action could be the synergistic arrest of the cell cycle, induction of apoptosis, activation of caspases-3,8and9, and down-regulation bcl-2expression. So, it can be indicated that the combination of Jieyoushen with5-FU exerted a synergistic anti-cancer effect on HCC growth, via the impact on the proteins of mitochondrial signaling pathway and the positive film, produced by Jieyoushen, which had a mechanical shielding effect on tumor cell membrane. So Jieyoushen will be a useful ancillary drug to improve the effectiveness of chemotherapeutic agents in the treatment of live cancer,which might be useful for the further development of anticancer drugs.
方法：在本研究中,体外培养SMMC-7721人肝癌细胞,R15大鼠肝癌细胞,使用不同浓度的有机硅季铵盐、不同浓度的5-FU及两药联合处理细胞,应用细胞形态观察、MTT比色法、Hochest染色、透射电镜、细胞周期、流式细胞术(Flow CytoMeter,FCM)和Western免疫印迹(Western blotting)等方法,研究洁悠神、5-FU及两药联合对肝癌细胞的作用。
结果：用不同浓度的药物处理两种肝癌细胞不同时间,细胞形态学观察肿瘤细胞表现为脱壁、变小和皱缩等凋亡现象；透射电镜观察发现细胞出现凋亡小体,MTT比色试验结果表明有机硅季铵盐对SMMC-7721人肝癌细胞,R15大鼠肝癌细胞的增殖活性有明显的抑制作用；FCM结果显示SMMC-7721人肝癌细胞,R15大鼠肝癌细胞在药物处理后凋亡细胞数明显增加,并且对抑制肿瘤细胞增殖作用及诱导肿瘤细胞凋亡作用随着药物作用时间和药物浓度的增加随之增加；Western blotting结果表明Bax、Caspase3、 Caspase8蛋白表达增加,而Bcl-2蛋白表达降低。
结论：有机硅季铵盐可能是一个有效的抗肿瘤药物；有机硅季铵盐联合5-FU表现出协同抑制效果;联合用药的作用机制为抑制细胞周期,诱导细胞凋亡,激活凋亡蛋白caspases-3、caspases-8和caspases-9,并下调bcl-2的表达,通过影响线粒体凋亡途径的基因表达,促进肿瘤细胞凋亡以达到抗肿瘤的效果；本研究将为抗肿瘤药物的研发提供新思路。
Purpose:There are still some difficulties we faced in the clinical treatment of HCC. The implantation metastasis in liver cancer operation is an urgent problem needed to be solved. In this study, we have investigated the effects of individual and joint action of organic silicone quaternary ammonium salt (Jieyoushen) and5-fluorouracil (5-FU) in human hepatocellular carcinoma SMMC7721cells lines and R15cell lines of rat in vitro. Here we assessed the characteristics of the drugs to explore the effects of individual and joint action of Jieyoushen and5-FU.
Methods:MTT assay was used to investigate the inhibitory effects of these agents. Electron microscopy and Hoechst33342staining were used to observe the morphological changes of liver cell lines treated with Jieyoushen and5-FU. Flow cytometry were performed to detect the cycle and apoptosis of liver cell lines with Jieyoushen and5-FU. The expression of caspases-3and8, bax, bcl-2, and survivin protein in these cells were determined by western blotting.
Results:The results of MTT assays showed that single and joint action Jieyoushen and5-FU inhibited the proliferation of liver carcinoma cell lines in a dose-and time-dependent manner respectively. And electron microscopy and Hoechst33342staining showed that characteristic apoptotic bodies were visible in apoptotic cell treated with Jieyoushen and5-FU. Flow cytometry results indicated that the percentages of cells at G0/G1phase gradually increased, while gradually decreased during S phase after the treatment. The medication leds to the changes on expression of proteins caspases-3,-8, bax, bcl-2and survivin. Compared with the control group, the expression levels of bax, caspase-8and caspase-3protein increased significantly in the SMMC7721and R15cells after24hours treatment, meanwhile, the bcl-2protein expression decreased significantly.
Conclusions:It can be concluded that the combination of Jieyoushen with5-FU showed a better inhibitory effect than either agent alone. The mechanism of action could be the synergistic arrest of the cell cycle, induction of apoptosis, activation of caspases-3,8and9, and down-regulation bcl-2expression. So, it can be indicated that the combination of Jieyoushen with5-FU exerted a synergistic anti-cancer effect on HCC growth, via the impact on the proteins of mitochondrial signaling pathway and the positive film, produced by Jieyoushen, which had a mechanical shielding effect on tumor cell membrane. So Jieyoushen will be a useful ancillary drug to improve the effectiveness of chemotherapeutic agents in the treatment of live cancer,which might be useful for the further development of anticancer drugs.
引文
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