PI3K抑制剂联合Ad-PTEN对裸鼠移植胶质瘤的治疗作用

The Effects of combined therapy of Phosphatidylinositol 3p-Kinase inhibitor and Ad-PTEN in human glioma nude mice model

目的本研究旨在观察磷脂酰肌醇3-激酶(PI3K)抑制剂LY294002联合含PTEN基因的重组腺病毒(Ad-PTEN)对人脑胶质瘤裸鼠移植瘤的抗肿瘤作用,初步探讨其可能的作用机制。方法将实验动物24只随机分为4组,即胶质瘤模型给予DMSO对照组、空载对照组、LY294002治疗组及LY294002与Ad-PTEN联合治疗组。皮下接种LN229人脑胶质瘤细胞建立胶质瘤裸鼠皮下移植瘤模型,定期测量动物体质量及肿瘤直径;应用免疫组化法检测肿瘤细胞的PTEN、p-Akt、PCNA、CyclinD1、Caspase-3、MMP-2、p-FAK的表达水平。结果联合治疗组对人脑胶质瘤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),p-Akt、CyclinD1、MMP2、p-FAK的表达均显著下降(均P<0.05)。结论LY294002与Ad-PTEN联合治疗可以提高对裸鼠移植人脑胶质瘤的抑制作用。

Objective Increasing evidence suggest that aberrant activation of PI3K/Akt is involved in many human cancers,and that inhibition of the PI3K/Akt pathway might be a promising strategy for cancer therapy.The study is to evaluate the effects of combined therapy of PI3K inhibitor （LY294002） and Ad-PTEN in athymic mice xenogeneic transplant model of human glioma and to reveal the possible mechanisms involved.Methods Twenty-four athymic mice were randomly divided into 4 groups （DMSO、Ad-vector plus DMSO、LY294002 alone and Ad-PTEN plus LY294002）,and were treated,respectively.Athymic mice xenogeneic transplant model was established by inoculation （sc） with LN229 glioma cells.Body mass （BM） and diameter of tumor mass were measured.Furthermore,The protein expressions of PTEN、p-Akt、CyclinD1、Caspase-3、MMP-2、p-FAK in tumor tissues were analyzed with immunohistochemistry.Results The tumor-inhibiting rate of was significantly higher in Ad-PTEN plus LY294002 than in the LY294002 alone （92.46 vs 65.59%）（P0.05）.The protein expressions of PTEN and Caspase-3 were significantly higher,while PCNA、CyclinD1、bcl-2 and MMP-2、p-FAK was significantly lower in Ad-PTEN plus LY294002 group than in the other three groups （P0.05）.Conclusions LY294002 plus Ad-PTEN achieve better outcome than either alone in treating glioma possibly through enhancement of the inhibitory action of PI3K/Akt pathway and Ad-PTEN pathway.