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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。
BACKGROUND AND OBJECTIVE At present, more and more evidences indicate that the abnormal activation of PI3K / AKT is involved in the development of human tumors. Therefore, targeting the PI3K / AKT pathway is expected to become a strategy for cancer therapy. The purpose of this study was to investigate the antitumor effect of PI3K inhibitor LY294002 combined with paclitaxel on lung cancer xenografts in nude mice and to explore its possible mechanism and to provide experimental data for the clinical treatment of lung cancer. Methods The experimental animals were randomly divided into three groups: lung cancer model group, paclitaxel treatment group and LY294002 combined with paclitaxel treatment group. The A549 lung adenocarcinoma cells were inoculated subcutaneously to establish a subcutaneous xenograft model of lung cancer in nude mice. The body weight and tumor diameter were measured regularly. The expression of CyclinD1, bcl-2 and bax proteins were analyzed by immunohistochemistry. Results The inhibitory effect of LY294002 combined with paclitaxel on lung cancer xenografts in nude mice was significantly higher than that in control group and paclitaxel treatment group (P <0.01). The expression of bax protein in tumor tissue was significantly higher than that in control group and paclitaxel-treated group (P = 0.021 , P = 0.001), while the expression of bcl-2 protein was significantly lower than that of the control group (P = 0.014). CyclinD1 expression was significantly lower than the control group and paclitaxel treatment group (P = 0.000, P = 0.002). Conclusion LY294002 can significantly enhance the therapeutic effect of paclitaxel on lung cancer. LY294002 enhanced bax, inhibition of CyclinD1 expression may be an important reason for suppression of tumor cell proliferation.