罗格列酮增强顺铂对肺腺癌裸鼠移植瘤生长的抑制作用

目的观察罗格列酮(ROZ)和顺铂(DDP)合用对人肺腺癌A549细胞裸小鼠移植瘤生长的抑制作用,并初步探讨其作用机制。方法采用A549细胞株建立人肺腺癌裸鼠模型,将28只成瘤雌裸小鼠随机分成7组:①对照组(生理盐水0.2ml);②DDP低剂量组(1mg.kg-1);③DDP高剂量组(4mg.kg-1);④ROZ低剂量组(10mg.kg-1);⑤ROZ高剂量组(30mg.kg-1);⑥DDP低剂量组+ROZ低剂量组;⑦DDP低剂量组+ROZ高剂量组,隔天腹腔注射给药,共8次。于最后一次给药后48h处死各组小鼠,收集瘤标本行光镜观察,免疫组化检测PPARγ、PTEN和pAkt蛋白表达情况。结果①各实验组肿瘤的生长明显受到抑制,瘤质量明显低于对照组(P<0.01)。低、高剂量ROZ联合用药组较低剂量顺铂组抑瘤作用明显增强(P<0.05),其瘤重抑制率分别为52.11%和83.8%。②免疫组化:低、高剂量罗格列酮组与对照组比较,PPARγ、PTEN的表达上调,而pAkt的表达呈现下调,差异具有显著性(P<0.05),联合用药组该调节作用进一步增强(P=0.00)。③不良反应:高剂量顺铂组出现不良反应,其余各组无明显不良反应。结论罗格列酮能够增强顺铂对人肺腺癌A549细胞裸鼠移植瘤生长的抑制作用,其作用机制可能与罗格列酮激活PPARγ,上调PTEN的表达和抑制pAkt的表达有关。

Inhibitory effects of rosiglitazone enhances cisplatin on growth of lung adenocarcinoma in nude mice

Aim To investigate the effects of rosiglitazone(ROZ)combined with cisplatin(DDP)on the growth of transplanted lung adenocarcinoma in mice and the corresponding mechanism.Methods The human lung adenocarcinoma mode was established with A549 cell in nude mice.Twenty eight female Balb/c-nu mice with lung adenocarcinoma were randomly divided into seven groups.① control group;② low-dose DDP group(1 mg·kg-1);③ high-dose DDP group(4 mg·kg-1);④ low-dose ROZ group(10 mg·kg-1);⑤ high-dose ROZ group(30 mg·kg-1);⑥ low-dose DDP plus low-dose ROZ group;⑦ low-dose DDP plus high-dose ROZ group;all the mice were sacrificed at 48 h after the last injection.Subcutaneous tumor was subjected to histological examination.Expressions of PPARγ、PTEN and pAkt in tumor tissues were detected by immunohistochemistry.Results ① In every treatment group tumor growth was suppressed significantly.Intraperitoneal injection of low and high-dose DDP,low and high-dose ROZ,low-dose DDP plus low-dose ROZ and low-dose DDP plus high-dose ROZ group resulted in a significant inhibition of the growth of A549 cells in vivo compared with that of control group(P<0.01).The anti-tumor effect of DDP plus ROZ was sig-nificantly enhanced compared with low-dose DDP(P<0.05),The inhibitory rate was 52.11% and 83.8%,respectively.② Immunohistochemistry:expression of PPARγand PTEN increased in every ROZ-treatment group,however,expression of pAkt decreased in every ROZ-treatment group.The difference was significant compared with control(P<0.01).This difference of DDP plus ROZ was significantly enhanced compared with control group(P=0.00).③ Adverse reaction:control,low-dose DDP,low and high-dose ROZ,DDP plus ROZ group did not show significant adverse reaction,while high dose DDP group showed some adverse reaction.Conclutions DDP combined with ROZ can significantly inhibit the growth of transplanted lung adenocarcinoma in mice in vivo,the mechanism of which is associated with the activation of PPARγ,up-regulation of the PTEN and down-regulation of the pAkt.