氯喹体外抗肝细胞癌作用的实验研究及机制探讨
摘要
肝细胞癌是目前严重威胁人类生命安全的疾病之一。寻求高效低毒的抗肿瘤药物及治疗方法一直是科学界研究的热点。氯喹是老药,具有广泛的生理学效应,以往主要用来治疗疟疾、自身免疫性疾病等,近年来发现氯喹具有治疗肿瘤的作用。本研究旨在研究氯喹的抗肝细胞癌作用并对其作用机制进行探讨。采用MTT法检测氯喹对人肝细胞癌HepG2细胞生长抑制作用;采用流式细胞术检测氯喹对人肝细胞癌HepG2细胞周期和凋亡的影响;采用免疫印迹法检测氯喹对HepG2细胞周期蛋白cyclinB1及NF-кB、p-IкBa、ERK、p-JNK和P38蛋白表达水平的影响。结果表明,氯喹可抑制HepG2细胞生长,诱导细胞发生G2/M期阻滞而影响细胞周期进程以及通过抑制HepG2细胞周期蛋白cyclinB1表达、抑制NF-кB、p-IкBa及ERK和诱导p-JNK蛋白表达水平促进细胞凋亡和抑制细胞增殖有关。本研究结果将为肝细胞癌的治疗提供新的药物,并且对老药氯喹用于治疗肝细胞癌的临床应用提供重要的实验依据。
Up to date, hepatocellular carcinoma therapy is still one of the serious problems that puzzle the scientists in the world. It is an important topic to seek an efficient way to treat hepatocellular carcinoma in the study of hepatocellular carcinoma. In this study, we explored the topic.
1. Influence of chloroquine on apoptosis and cell cycle and the proliferation.
First: HepG2 cells were divided into six groups:control group and chloroquine (8、16、32、64 and 128uM ) groups. The cell viability was determined by MTT; The cell cycle and apoptosis was detected by flow cytometry. Results showed that the cell viabilities were inhibited significantly 24h after chloroquine (32-128 uM) or 48-72h after chloroquine (8-128 uM) (P<0.01) ,compared with control group; HepG2 cells treated with chloroquine (32-128uM) for 24h were obviously arrested at G2/M phases,compared with control group (P<0.01). we concluded that chloroquine can suppress the activities of hepatoma HepG2 cells by inhibiting cells proliferation, inducing cells apoptosis and arresting cell cycle in vitro. So chloroquine is probably the drug for hepatocellular carcinoma.
2. The study found that cell apoptosis was different with different chloroquine and blockers.The apoptosis increased when the cells were treated by chloroquine and PDTC;The apoptosis decreased when the cells were treated by chloroquine and sp600125;The apoptosis was not changed by chloroquine and SB203580 and PD98059.
3. Measurement of protein level
Four protein were studied, including NF-кB、p-IкBa、P38、ERK and p-JNK. Western Blot assay was employed for the measurement of protein level 3.1 Changes in NF-кB protein expression
Results showed that NF-кB protein expression tended to decrease with the increase of chloroquine , the most effective inhibitory occurred at 128 uM. The inhibitor of NF-кB increased the chloroquine effect.
3.2 Changes in p-IкBa protein expression
Results showed that p-IкBa protein expression tended to decrease with the increase of chloroquine , the most effective inhibitory occurred at 128 uM.
3.3 Changes in P38 protein expression
Results showed that no any change was observed in P38 protein expression.
3.4 Changes in p-JNK protein expression
Results showed that p-JNK protein expression tended to increase with the increase of chloroquine , the most effection occurred at 128 uM.
3.5 Changes in ERK protein expression
Results showed that ERK protein expression tended to decrease with the increase of chloroquine , the most effective inhibitory occurred at 128 uM. 3.6 By application of blockers, the study further confirmed that the apoptosis was increased due to the inhibitory of NF-кB and p-IкBαby chloroquine. The apoptosis was increased due to the increase of p-JNK by chloroquine.The proliferation of cells was inhibited owing to the ERK protein decrease by chloroquine.
Taken together, the chloroquine can suppress the activities of hepatoma HepG2 cells by inhibiting cells proliferation, inducing cells apoptosis and arresting cell cycle in vitro. So chloroquine is probably the drug for hepatocellular carcinoma. By inhibiting the protein expression of NF-кB、p-JNK and ERK. But there was no change in the express of P38 protein.
Up to date, hepatocellular carcinoma therapy is still one of the serious problems that puzzle the scientists in the world. It is an important topic to seek an efficient way to treat hepatocellular carcinoma in the study of hepatocellular carcinoma. In this study, we explored the topic.
1. Influence of chloroquine on apoptosis and cell cycle and the proliferation.
First: HepG2 cells were divided into six groups:control group and chloroquine (8、16、32、64 and 128uM ) groups. The cell viability was determined by MTT; The cell cycle and apoptosis was detected by flow cytometry. Results showed that the cell viabilities were inhibited significantly 24h after chloroquine (32-128 uM) or 48-72h after chloroquine (8-128 uM) (P<0.01) ,compared with control group; HepG2 cells treated with chloroquine (32-128uM) for 24h were obviously arrested at G2/M phases,compared with control group (P<0.01). we concluded that chloroquine can suppress the activities of hepatoma HepG2 cells by inhibiting cells proliferation, inducing cells apoptosis and arresting cell cycle in vitro. So chloroquine is probably the drug for hepatocellular carcinoma.
2. The study found that cell apoptosis was different with different chloroquine and blockers.The apoptosis increased when the cells were treated by chloroquine and PDTC;The apoptosis decreased when the cells were treated by chloroquine and sp600125;The apoptosis was not changed by chloroquine and SB203580 and PD98059.
3. Measurement of protein level
Four protein were studied, including NF-кB、p-IкBa、P38、ERK and p-JNK. Western Blot assay was employed for the measurement of protein level 3.1 Changes in NF-кB protein expression
Results showed that NF-кB protein expression tended to decrease with the increase of chloroquine , the most effective inhibitory occurred at 128 uM. The inhibitor of NF-кB increased the chloroquine effect.
3.2 Changes in p-IкBa protein expression
Results showed that p-IкBa protein expression tended to decrease with the increase of chloroquine , the most effective inhibitory occurred at 128 uM.
3.3 Changes in P38 protein expression
Results showed that no any change was observed in P38 protein expression.
3.4 Changes in p-JNK protein expression
Results showed that p-JNK protein expression tended to increase with the increase of chloroquine , the most effection occurred at 128 uM.
3.5 Changes in ERK protein expression
Results showed that ERK protein expression tended to decrease with the increase of chloroquine , the most effective inhibitory occurred at 128 uM. 3.6 By application of blockers, the study further confirmed that the apoptosis was increased due to the inhibitory of NF-кB and p-IкBαby chloroquine. The apoptosis was increased due to the increase of p-JNK by chloroquine.The proliferation of cells was inhibited owing to the ERK protein decrease by chloroquine.
Taken together, the chloroquine can suppress the activities of hepatoma HepG2 cells by inhibiting cells proliferation, inducing cells apoptosis and arresting cell cycle in vitro. So chloroquine is probably the drug for hepatocellular carcinoma. By inhibiting the protein expression of NF-кB、p-JNK and ERK. But there was no change in the express of P38 protein.
引文
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