食道通结方对食管癌裸鼠移植瘤细胞增殖及凋亡的影响
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摘要
目的:通过体内实验观察食道通结方对食管癌裸鼠移植瘤增殖、凋亡相关蛋白表达的影响,进一步明确该方治疗食管癌的作用机制。方法:裸鼠皮下接种食管癌TE-1瘤株,造模成功后随机分为模型组、中药组、顺铂组、中药+顺铂组,各组分别予0.9%Na Cl溶液、中药食道通结方、顺铂、中药食道通结方+顺铂干预,共28 d。观察各组裸鼠皮下移植瘤生长情况,检测肿瘤细胞增殖指数、凋亡指数的变化以及移植瘤细胞内增殖、凋亡相关蛋白Stat3、P53、Bcl-2、Bax、Caspase3表达情况。结果:与模型组比较,各药物组的平均移植瘤体积及瘤重均明显降低(P<0.01),其中中药+顺铂组显著低于中药组及顺铂组(P<0.01)。各药物组的皮下移植瘤细胞增殖指数均显著降低(P<0.01),其中顺铂组明显低于中药组(P<0.01),而中药+顺铂组降低更显著(P<0.01);各药物组的皮下移植瘤细胞凋亡指数均明显升高(P<0.01),其中中药+顺铂组显著高于中药组及顺铂组(P<0.01)。各药物组的肿瘤组织中Stat3、Bcl-2表达均明显下降,P53、Bax、Caspase3表达均显著增加,其中中药+顺铂组变化更为明显。结论:食道通结方具有抑制食管癌细胞株TE-1皮下移植瘤细胞增殖、促进其凋亡的作用,并能增强顺铂抑制肿瘤细胞生长的作用,其可能与下调食管癌细胞株TE-1中Stat3、Bcl-2的表达,上调P53、Bax、Caspase3的表达相关。
Objective: To observe the effects of Shidao Tongjie Decoction on the expressions of proliferation-related and apoptosisrelated proteins of esophageal cancer xenografts in nude mice in vivo,and further clarify the mechanism of Shidao Tongjie Decoction in the treatment of esophageal cancer. Methods: Nude mice were inoculated subcutaneously with esophageal cancer TE-1 tumor cells. After successful modeling,the nude mice were randomly divided into the model group,Chinese medicine group,cisplatin group and Chinese medicine plus cisplatin group,which respectively treated with 0.9% Na Cl solution,Shidao Tongjie Decoction,cisplatin and Shidao Tongjie Decoction combined with cisplatin,with a course of 28 days. The growth of transplanted tumors in nude mice of each group was observed.The changes on the tumor cell proliferation index and apoptosis index and the protein expressions of Stat3,P53,Bcl-2,Bax and Caspase3 in transplanted tumor cells were detected. Results: Compared with the model group,the average transplanted tumor volume and tumor weight of all drug treatment groups were significantly decreased( P<0.01),and the volume and tumor weight of the Chinese medicine plus cisplatin group were significantly lower than those of the Chinese medicine group and the cisplatin group( P<0.01). The proliferation index of subcutaneously transplanted tumor cells in all drug treatment groups was significantly decreased( P<0.01),and the index in the cisplatin group was significantly lower than that in the Chinese medicine group( P<0.01),while the decrease in the Chinese medicine plus cisplatin group was more significant( P<0.01). The apoptosis index of subcutaneously transplanted tumor cells in all drug treatment groups was significantly increased( P<0.01),and the index in the Chinese medicine plus cisplatin group was significantly higher than that in the Chinese medicine group and the cisplatin group( P<0.01). The expressions of Stat3 and Bcl-2 in the tumor tissue of all drug treatment groups were significantly decreased,and the expressions of P53,Bax and Caspase3 were significantly increased. The changes on the expressions in the Chinese medicine plus cisplatin group were more significant. Conclusion: Shidao Tongjie Decoction inhibits the proliferation of esophageal cancer TE-1 cell line and promotes its apoptosis. It can also enhance the inhibitory effects of cisplatin on the growth of tumor cells. This may be related to the down-regulation of Stat3 and Bcl-2 expressions and up-regulation of P53,Bax and Caspase3 expressions in esophageal cancer TE-1 cell line.
Objective: To observe the effects of Shidao Tongjie Decoction on the expressions of proliferation-related and apoptosisrelated proteins of esophageal cancer xenografts in nude mice in vivo,and further clarify the mechanism of Shidao Tongjie Decoction in the treatment of esophageal cancer. Methods: Nude mice were inoculated subcutaneously with esophageal cancer TE-1 tumor cells. After successful modeling,the nude mice were randomly divided into the model group,Chinese medicine group,cisplatin group and Chinese medicine plus cisplatin group,which respectively treated with 0.9% Na Cl solution,Shidao Tongjie Decoction,cisplatin and Shidao Tongjie Decoction combined with cisplatin,with a course of 28 days. The growth of transplanted tumors in nude mice of each group was observed.The changes on the tumor cell proliferation index and apoptosis index and the protein expressions of Stat3,P53,Bcl-2,Bax and Caspase3 in transplanted tumor cells were detected. Results: Compared with the model group,the average transplanted tumor volume and tumor weight of all drug treatment groups were significantly decreased( P<0.01),and the volume and tumor weight of the Chinese medicine plus cisplatin group were significantly lower than those of the Chinese medicine group and the cisplatin group( P<0.01). The proliferation index of subcutaneously transplanted tumor cells in all drug treatment groups was significantly decreased( P<0.01),and the index in the cisplatin group was significantly lower than that in the Chinese medicine group( P<0.01),while the decrease in the Chinese medicine plus cisplatin group was more significant( P<0.01). The apoptosis index of subcutaneously transplanted tumor cells in all drug treatment groups was significantly increased( P<0.01),and the index in the Chinese medicine plus cisplatin group was significantly higher than that in the Chinese medicine group and the cisplatin group( P<0.01). The expressions of Stat3 and Bcl-2 in the tumor tissue of all drug treatment groups were significantly decreased,and the expressions of P53,Bax and Caspase3 were significantly increased. The changes on the expressions in the Chinese medicine plus cisplatin group were more significant. Conclusion: Shidao Tongjie Decoction inhibits the proliferation of esophageal cancer TE-1 cell line and promotes its apoptosis. It can also enhance the inhibitory effects of cisplatin on the growth of tumor cells. This may be related to the down-regulation of Stat3 and Bcl-2 expressions and up-regulation of P53,Bax and Caspase3 expressions in esophageal cancer TE-1 cell line.
引文
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[13]CAO Y Y,YU J,LIU T T,et al.Plumbagin inhibits the proliferation and survival of esophageal cancer cells by blocking STAT3-PLK1-AKT signaling[J].Cell Death Dis,2018,9(2):17.
[14]GRUBER E S,BIRNER P,MERKEL O,et al.Abstract 4463:The coactivator oncogene AF1Q associates with STAT3 activation downstream of MET action in gastro-esophageal cancer patients[J].Cancer Res,2017,77(13 Suppl):4463.
[15]HUA P,SUN M,ZHANG G,et al.Costunolide Induces Apoptosis through Generation of ROS and Activation of P53 in Human Esophageal Cancer Eca-109 Cells[J].J Biochem Mol Toxicol,2016,30(9):462-469.
[16]LEE I H,KAWAI Y,FERGUSSON M M,et al.Atg7 modulates p53activity to regulate cell cycle and survival during metabolic stress[J].Science,2012,336(6078):225-228.
[17]HUANG Y,FU Z,DONG W,et al.Serum starvation-induces downregulation of Bcl-2/Bax confers apoptosis in tongue coating-related cells in vitro[J].Mol Med Rep,2018,17(4):5057-5064.
[18]CHEN Y,SUN M,DING J,et al.SM-1,a novel PAC-1 derivative,activates procaspase-3 and causes cancer cell apoptosis[J].Cancer Chemother Pharmacol,2016,78(3):643-654.
[2]张铭,李蕾,崔清,等.食道通结方对食管癌细胞株TE-1增殖和凋亡的影响[J].上海中医药杂志,2014,48(6):92-95.
[3]崔清,董昀,张铭,等.食道通结方对裸鼠食管癌移植瘤中TE-1细胞增殖及凋亡的影响[J].上海中医药杂志,2016,50(5):65-69.
[4]郝淑兰,刘丽坤,王晞星,等.人胃癌SGC7901/VCR裸鼠移植瘤模型的建立及耐药性检测[J].世界中西医结合杂志,2013,8(4):358-360.
[5]李仪奎.中药药理实验方法学[M].上海:上海科学技术出版社,2006:38-42.
[6]ARNOLD M,SOERJOMATARAM I,FERLAY J,et al.Global incidence of oesophageal cancer by histological subtype in 2012[J].Gut,2015,64(3):381-387.
[7]CHEN W,ZHENG R,ZENG H,et al.Annual report on status of cancer in China,2011[J].Chin J Cancer Res,2015,27(1):2-12.
[8]林琳,曹鹏.放化疗结合中医药治疗食管癌的临床研究进展[J].世界华人消化杂志,2012,20(35):3505-3509.
[9]金长娟,李蕾,崔清,等.食管癌术后中西医综合治疗临床观察[J].肿瘤,2003,23(5):429-431.
[10]崔清,郭毅峻,张铭,等.食道通结方联合化疗治疗中晚期食管癌术后患者临床疗效观察[J].上海中医药大学学报,2015,29(6):29-32.
[11]FLORES E R.Commentary on“Apoptosis,p53,and Tumor Cell Sensitivity to Anticancer Agents”[J].Cancer Res,2016,76(23):6763-6764.
[12]JANSSON S,BENDAHL P O,LARSSON A M,et al.Prognostic impact of circulating tumor cell apoptosis and clusters in serial blood samples from patients with metastatic breast cancer in a prospective observational cohort[J].BMC Cancer,2016,16(1):433.
[13]CAO Y Y,YU J,LIU T T,et al.Plumbagin inhibits the proliferation and survival of esophageal cancer cells by blocking STAT3-PLK1-AKT signaling[J].Cell Death Dis,2018,9(2):17.
[14]GRUBER E S,BIRNER P,MERKEL O,et al.Abstract 4463:The coactivator oncogene AF1Q associates with STAT3 activation downstream of MET action in gastro-esophageal cancer patients[J].Cancer Res,2017,77(13 Suppl):4463.
[15]HUA P,SUN M,ZHANG G,et al.Costunolide Induces Apoptosis through Generation of ROS and Activation of P53 in Human Esophageal Cancer Eca-109 Cells[J].J Biochem Mol Toxicol,2016,30(9):462-469.
[16]LEE I H,KAWAI Y,FERGUSSON M M,et al.Atg7 modulates p53activity to regulate cell cycle and survival during metabolic stress[J].Science,2012,336(6078):225-228.
[17]HUANG Y,FU Z,DONG W,et al.Serum starvation-induces downregulation of Bcl-2/Bax confers apoptosis in tongue coating-related cells in vitro[J].Mol Med Rep,2018,17(4):5057-5064.
[18]CHEN Y,SUN M,DING J,et al.SM-1,a novel PAC-1 derivative,activates procaspase-3 and causes cancer cell apoptosis[J].Cancer Chemother Pharmacol,2016,78(3):643-654.