磷脂酰肌醇-3激酶抑制剂LY294002增加紫杉醇对肺癌裸鼠移植瘤的治疗作用

背景与目的目前越来越多的证据表明PI3K/AKT的异常活化参与人类肿瘤的发生发展,因此针对PI3K/AKT路径有望成为肿瘤治疗的策略。此研究旨在观察PI3K抑制剂LY294002联合紫杉醇对肺癌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提供实验资料。方法将实验动物随机分为3组,即肺癌模型组、紫杉醇治疗组及LY294002与紫杉醇联合治疗组。皮下接种A549肺腺癌细胞建立肺癌裸鼠皮下移植瘤模型,定期测量动物体重及肿瘤直径;应用免疫组织化学方法分析CyclinD1及bcl-2,bax蛋白水平的表达。结果LY294002与紫杉醇联合治疗组对肺癌裸鼠移植瘤抑制作用较对照组及紫杉醇治疗组均明显增强(P<0.01);瘤组织bax蛋白表达水平较对照组及紫杉醇治疗组均增强(P=0.021,P=0.001),而bcl-2蛋白表达水平较对照组明显降低(P=0.014)。CyclinD1表达较对照组及紫杉醇治疗组均明显降低(P=0.000,P=0.002)。结论LY294002可显著增强紫杉醇对肺癌的治疗作用。LY294002增强bax、抑制CyclinD1表达可能是肿瘤细胞增殖受抑的重要原因。

Effects of combined therapy of Phosphatidylinositol 3p-Kinase and Paclitaxel in human lung cancer nude mice model

Background and objective Increasing evidence suggests 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 aims of this study is to evaluate the effects of combined therapy of Phosphatidylinositol 3-Kinase inhibitor(LY294002 ) and Paclitaxel in athymic mice xenogeneic transplant model of lung cancer and to reveal the possible mechanisms involved.Methods Eighteen athymic mice were randomly divided into 3 groups(control,paclitaxel alone and paclitaxel plus LY294002),and were treated respectively.Athymic mice xenogeneic transplant model was established by inoculation(sc) with A549 lung cancer cells.Body mass(BM) and diameter of tumor mass were measured.Furthermore,the protein expressions of CyclinD1,bcl-2 and bax in tumor tissues were analyzed with immunohistochemistry.Results The tumor-inhibiting rate of paclitaxel plus LY294002(92.47%) was significantly higher than the paclitaxel alone(65.59%)(P<0.05).The protein expression of bcl-2 in paclitaxel plus LY294002 group were significantly higher,while bax was significantly lower than that in the other two groups(P<0.05).The protein expression of CyclinD1 was significantly lower than the control group(P<0.05).Conclusion LY294002 can enhance the effects of paclitaxel in the treatment of lung cancer and CyclinD1,bcl-2 and bax may be involved in its inhibitory effects.