三叶青总黄酮逆转吉非替尼耐药肺腺癌细胞的耐药性

Reversal effects and mechanisms of Flavonoids from Tetrastigma hemsleyanum on drug resistance in gefitinib-resistant lung cancer cells

目的:探讨三叶青总黄酮(FTH)逆转吉非替尼(GEF)耐药肺腺癌细胞的耐药性及其初步机制。方法:采用MTT法,检测FTH对GEF耐药A549/GR细胞增殖的影响;采用流式细胞技术检测FTH对A549/GR细胞凋亡及周期的影响;建立A549/GR细胞荷瘤小鼠模型,观察两药联用后的体内抑瘤效果;采用Western blot法检测瘤组织PI3K/Akt信号通路关键蛋白(PTEN、PI3K、p-PI3K、AKT、p-AKT)的表达情况。结果:与单用GEF相比,FTH联合GEF给药可显著抑制A549/GR细胞增殖(P<0.05),诱导A549/GR细胞凋亡(P<0.05),使细胞停滞在G 0/G 1期。体内实验结果表明,两者联合可显著抑制裸鼠A549/GR移植瘤的生长(P<0.05),并显著降低瘤组织p-PI3K和p-AKT表达(P<0.05),升高PTEN蛋白表达(P<0.05)。结论:FTH可逆转A549/GR细胞对GEF的耐药性,其作用机制可能与调控PTEN/PI3K/AKT通路有关。

AIM:To investigate the sensitization of flavonoids from Tetrastigma hemsleyanum(FTH)on gefitinib(GEF)-resistant lung adenocarcinoma cells.METHODS:The viabilities of A549 and A549/GR cells treated with FTH and GEF were detected by MTT method.The apoptotic rates and cell cycles of A549/GR cells treated with FTH and GEF were detected by Flow cytometry.The anti-tumor effects of flavonoids from FTH and GEF were assayed in A549/GR tumor-bearing mice.The expressions of proteins(PTEN,PI3K,p-PI3K,AKT,p-AKT)were detected by Western blot analysis.RESULTS:Compared with GEF group,FTH significantly enhanced the inhibition of GEF on the proliferation of A549/GR cells(P<0.05).Combination with FTH and GEF significantly increased the apoptosis of A549/GR cells which were arrested at the G 0/G 1 stage(P<0.05).The in vivo results showed that combination with FTH and GEF significantly inhibited the tumor growth of A549/GR in mice(P<0.05).Furthermore,this combination significantly downregulated the expressions of p-PI3K and p-AKT(P<0.05),but upregulated the expressions of PTEN(P<0.05).CONCLUSION:FTH increases the sensitivity to gefitinib by modulating PTEN/PI3K/AKT pathway in acquired GEF resistance of non-small cell lung cancer.