罗格列酮增强顺铂对人肺腺癌裸鼠移植瘤生长的抑制作用

Rosiglitazone enhanced growth inhibition of transplanted lung adenocarcinoma by Cisplatin in nude mice

目的探讨过氧化物酶体增殖物激活受体γ(PPARγ)配体罗格列酮(ROZ)与顺铂(DDP)联合应用对人肺腺癌细胞系A549裸鼠移植瘤的作用及机制。方法建立人肺腺癌细胞裸鼠移植瘤模型,28只荷瘤裸鼠随机分为7组,A组(对照组),B组(DDP1mg/kg),C组(DDP4mg/kg),D组(ROZ10mg/kg),E组(ROZ30mg/kg),F组(DDP1mg/kg+ROZ10mg/kg),E组(DDP1mg/kg+ROZ30mg/kg)。隔天腹腔注射给药,共10次,给药期间每4日测量皮下移植瘤的最长经和最短经,按标准公式:移植瘤体积(V)=最长径×最短径2×0.52计算瘤体积,绘制肿瘤生长曲线。实验末处死裸鼠,剥离皮下移植瘤,称量重量,计算瘤重抑制率;移植瘤组织标本SP免疫组织化学检测PPARγ、NFκB、Bcl-2蛋白的表达。结果罗格列酮和顺铂单独应用均能抑制裸鼠移植瘤的生长,呈剂量依赖性(P<0.01)。罗格列酮(30mg/kg)与低剂量顺铂(1mg/kg)联合应用具有协同效应(q=1.29)。ROZ处理后裸鼠移植瘤细胞PPARγ蛋白表达上调,NFκB、Bcl-2蛋白表达下调(P<0.001)。结论罗格列酮通过上调PPARγ蛋白表达,下调NFκB、Bcl-2蛋白表达增强顺铂抑制人肺癌裸鼠移植瘤生长。

[Objective] To investigate the synergistic effects of Rosiglitazone with Cisplatin on the growth of lung adenocarcinoma cell line A549 xenografted to nude mice.[Methotls] A549 cells were transplanted into nude mice, and twenty-eight xenografts were established successively. They were then randomly divided into 7 groups： A（control group）, B（Cisplatin 1 mg/kg）, C（Cisplatin 4 mg/kg）, D（Rosiglitazone 10 mg/kg）, E（Rosiglitazone 30 mg/kg）, F（Cisplatin 1 mg/kg ＋ Rosiglitazone 10 mg/kg）, G（Cisplatin 1 mg/kg ＋ Rosiglitazone 30 mg/kg）. Seven days after implantation, different treatments were served from the 4th day, and all mice were sacrificed after 29 days. The volumes of the transplanted tumors were measured every 4 days during the therapy. The minor growth inhibiting rates of each group were calculated. Moreover, the curves of tumor growth were drawn. Subcutaneous tumor PPARγ, Bcl-2 and NFκB were determined by immunohistochemical method with image analysis system. [Results] In each treatment group, tumor growth was suppressed significandy by intraperitoneal injection of Cisplatin, Rosiglitazone and their combination resulted in a significant inhibition on the growth of A549 cells in vivo （P 〈0.01）, the combination group （Cisplatin 1 mg/kg ＋ Rosiglitazone 30 mg/kg） showed synergic effect on inhibiting the growth of the xenografts with a q value of 1.29. Contrary to control group, the expression of subcutaneous tumor Bcl-2 and NFκB was obviously down-regulated and the PPARγ was up-regulated by Rosiglitazone and its combination with Cisplatin （P 〈0.001）. [Conclusion] The ligand of PPARγ Rosiglitazone enhances the inhibition of proliferation and induction of apoptosis by treatment with Cisplation in lung adenocarcinoma cells in nude mice in vivo. Activation of PPARγ protein and down-regulation of Bcl-2 and NFκB possibly play important roles in ehemosensitizng mechanism of Rosiglitazone in vivo.