LY294002联合Ad-PTEN对肺腺癌脑转移裸鼠移植瘤的治疗作用

LY294002 combined Ad-PTEN therapy for pulmonary adenocarcinoma brain metastasis innude mice model

目的观察PI3K(磷脂酰肌醇3-激酶)抑制剂2-(4-吗啉基)-8-苯基-4氢-1-苯并吡喃-4酮(LY294002)联合Ad-PTEN(含PTEN基因的重组腺病毒)对人肺腺癌脑转移裸鼠移植瘤的抗肿瘤作用,初步探讨其可能的作用机制,为临床有效治疗肺癌脑转移提供实验资料。方法将实验裸鼠24只随机分为4组,即DMSO对照组、空载病毒组、LY294002治疗组及LY294002与Ad-PTEN联合治疗组。肿瘤组织块直接皮下种植法建立肺腺癌裸鼠皮下移植瘤模型,定期测量动物体重及肿瘤直径;应用Western blotting法检测肿瘤细胞的PTEN、p-Akt、PI3K、CyclinD1、Bcl-2、Caspase-3、MMP-2、9、p-FAK的表达水平;结果 LY294002与Ad-PTEN联合治疗组对人肺腺癌脑转移裸鼠移植瘤抑制作用较对照组及LY294002治疗组均明显增强(均P<0.01);与对照组及LY294002治疗组比较联合治疗组Caspase-3、PTEN表达显著升高(均P<0.05),PI3K、p-Akt、CyclinD1、MMP2、9、p-FAK、Bcl-2的表达均显著下降(均P<0.05)。结论 LY294002与Ad-PTEN联合治疗可以显著提高对人肺腺癌脑转移裸鼠移植瘤的抑制作用。其机制可能与下调PI3K/AKT信号通路下游蛋白有关。

[ Objective] To observe the effects of combined therapy of PI3K inhibitor （LY294002） and Ad- PTEN in athymic mice xenogeneic transplant model of brain metastasis from pulmonary adenocarcinoma and to identifythe possible mechanisms involved. [Methods] Twenty-four athymic mice were randomly divided into 4 groups （control,DMSO,LY294002 alone and Ad-PTEN plus LY294002）, and were treated respectively. Athymic mice xenogeneic transplant model was established by inoculation （se） with tumor tissues directly. Body mass （BM） and diameter of tumor mass were measured. Furthermore, The protein expressions of PTEN,PI3K,p-AkI,CyclinD1,Bcl-2, Caspase-3,MMP-2,9, p-FAK in tumor tissues were analyzed by Western blotting. [ Results ] The lumorinhibiting rate of Ad-PTEN plus LY294002 was significantly higher than the LY294002 alone（P 〈0.05）. The protein expression of FFEN and caspase-3 in Ad-PTEN plus LY294002 group was significantly higher, while Pl3K,p-Akt,CyclinDl, Bcl-2,MMP-2,9,p-FAK weresignificantly lower than that in the other three groups （P 〈0.05）. [Conclusion] Combined therapy of LY294002 and Ad-FFEN can enhance the efficacy for brain metastasis from pulmonary adenocareinnma, the mechanisms may be related to the down-regulation of the Pl3K/AKTdownstream proteins expression.