多西他赛联合TRAIL诱导胃癌细胞凋亡的机制探讨
摘要
目的:肿瘤坏死因子相关凋亡诱导配体能够诱导多种肿瘤细胞发生凋亡,但并不是所有的肿瘤细胞都对其敏感。以往研究表明一些化疗药物能够增强TRAIL所诱导的肿瘤细胞凋亡。本实验旨在探讨多西他赛联合TRAIL体外诱导胃癌细胞凋亡的作用及可能机制。
方法:采用MTT法检测不同浓度(1、5、10、20、40μg/ml),不同时间(12、24、36、48h)下多西他赛的抗癌活性并计算其亚毒性剂量。用流式细胞仪检测多西他赛(亚毒性剂量)及TRAIL(200 ng/ml)单独及联合应用后SGC7901的凋亡率。RT-PCR法检测DR4、DR5、DcR1、DcR2、Caspase-8及Bcl-2 mRNA在加药前后的表达。
结果:对照组(C组)、亚毒性剂量的多西他赛(P组)、TRAIL(T组)及二者联合(T+P)作用24h后胃癌细胞的凋亡率分别为2.09%、10.65%、7.79%和24.51%,T+P组凋亡率明显升高,与C组、T组、P组两两比较,差异均具有显著性(P<0.05)。多西他赛处理组DR5表达增加。
结论:多西他赛与TRAIL具有协同抗胃癌作用,其机制可能与DR5 mRNA表达上调有关。
Objective:Tumor necrosis factor related apoptosis-inducing ligand (TRAIL)is a death receptor ligand that can induce apoptosis in a variety of cancer cell lines, but not all cancer cells.Past studies suggested that some Chemotherapeutic drugs intensified the sensitivity of TRAIL in inducing apoptosis.In this study,we investigate the effect and potential mechanism of combined Paclitaxe with TRAIL on apoptosis of human gastric cancer cell in vitro.
Methods:SGC7901cells were cultured with Paclitaxe at different concentrations(1,5,10,20,40μg/ml)and different time(12,24,36,48h), Methylhiazolyl tetrazolium(MTT) assay was used to measure the anticancer activity of Paclitaxe.The ability of TRAIL alone,aclitaxe alone and TRAIL in combination with Paclitaxe to induce apoptosis was measured by a flow cytometer.Expression of DR4,DR5, DcR1,DcR2,Caspase-8 and Bcl-2 mRNA was examined by RT-PCR.
Results:The apoptosis rate of control group( group),aclitaxe group(P group),TRAIL group(T group)and combination group(T+P)in 24h was respectively 2.09%,10.65%,7.79% and 24.51%.The apoptosis rate in T+P group was significantly higher than that in C group,T group and P group(P<0.05).Before exposure to Paclitaxe,DR5 mRNA expression was low and an increased expression of DR5 was found in SGC7901 cells after treatment with Paclitaxe.
Conclusion:Paclitaxe can enhance the effect of TRAIL in anticancer therapy and its mechanisms might be involved in the up-regulation of DR5 gene.
方法:采用MTT法检测不同浓度(1、5、10、20、40μg/ml),不同时间(12、24、36、48h)下多西他赛的抗癌活性并计算其亚毒性剂量。用流式细胞仪检测多西他赛(亚毒性剂量)及TRAIL(200 ng/ml)单独及联合应用后SGC7901的凋亡率。RT-PCR法检测DR4、DR5、DcR1、DcR2、Caspase-8及Bcl-2 mRNA在加药前后的表达。
结果:对照组(C组)、亚毒性剂量的多西他赛(P组)、TRAIL(T组)及二者联合(T+P)作用24h后胃癌细胞的凋亡率分别为2.09%、10.65%、7.79%和24.51%,T+P组凋亡率明显升高,与C组、T组、P组两两比较,差异均具有显著性(P<0.05)。多西他赛处理组DR5表达增加。
结论:多西他赛与TRAIL具有协同抗胃癌作用,其机制可能与DR5 mRNA表达上调有关。
Objective:Tumor necrosis factor related apoptosis-inducing ligand (TRAIL)is a death receptor ligand that can induce apoptosis in a variety of cancer cell lines, but not all cancer cells.Past studies suggested that some Chemotherapeutic drugs intensified the sensitivity of TRAIL in inducing apoptosis.In this study,we investigate the effect and potential mechanism of combined Paclitaxe with TRAIL on apoptosis of human gastric cancer cell in vitro.
Methods:SGC7901cells were cultured with Paclitaxe at different concentrations(1,5,10,20,40μg/ml)and different time(12,24,36,48h), Methylhiazolyl tetrazolium(MTT) assay was used to measure the anticancer activity of Paclitaxe.The ability of TRAIL alone,aclitaxe alone and TRAIL in combination with Paclitaxe to induce apoptosis was measured by a flow cytometer.Expression of DR4,DR5, DcR1,DcR2,Caspase-8 and Bcl-2 mRNA was examined by RT-PCR.
Results:The apoptosis rate of control group( group),aclitaxe group(P group),TRAIL group(T group)and combination group(T+P)in 24h was respectively 2.09%,10.65%,7.79% and 24.51%.The apoptosis rate in T+P group was significantly higher than that in C group,T group and P group(P<0.05).Before exposure to Paclitaxe,DR5 mRNA expression was low and an increased expression of DR5 was found in SGC7901 cells after treatment with Paclitaxe.
Conclusion:Paclitaxe can enhance the effect of TRAIL in anticancer therapy and its mechanisms might be involved in the up-regulation of DR5 gene.
引文
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[6] Galligan L,Longley DB,McEwan M,et al.Chemotherapy and TRAIL-mediated colon cancer cell death:the roles of p53,TRAIL receptors,and c-FLIP.Mol Cancer Ther. 2005;4(12):2026-36.
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[8] Ma Y,Lakshmikanthan V,Lewis RW,et al.Sensitization of TRAIL-resistant cells by inhibition of heat shock protein 90 with low-dose geldanamycin.Mol Cancer Ther. 2006,5(1):170-8.
[9] Elomaa L,Joensuu H,Kulmala J,et a1.Squamous cell Carcinoma is highly sensitive to taxel,a possible new radiation sensitizer.Acta Oldaryngal(Stockh),1995; 115(2):340-4.
[10] Pucci B,Bellincampi L,Tafani M,et al.Paclitaxel induces apoptosis in Saos-2 cells with CD95L upregulation and Bcl-2 phosphorylation.1999;252(1):134-43.
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[12] Keane MM,Ettenberg SA,Nau MM,et al.Chemotherapy augments TRAIL-induced apoptosis in breast cell lines. Cancer Res.1999;59(3):734-41.
[13] Odoux C,Albers A,Amoscato AA,et al.TRAIL,FasL and a blocking anti-DR5 antibody augment paclitaxel-induced apoptosis in human non-small-cell lung cancer. Int J Cancer.2002;97(4):458-65.
[14] 陈晓萍,薛兴奎,张沂平,等.紫杉醇对胃癌细胞作用及其机制的研究[J].肿瘤,2006,26(4):243-359.
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