IGF －1R 抑制剂 OSI －906对鼻咽癌细胞 SUNE －1放射增敏作用的研究

目的：探讨酪氨酸激酶抑制剂（TKI）OSI －906对鼻咽癌 SUNE －1细胞放疗增敏的作用机制。方法：MTT 检测 OSI －906对 SUNE －1细胞增殖的影响；Western blot 检测 X 线照射（IR）、OSI －906对 IGF －1R／AKT 和 IGF －1R／ERK 信号通路的影响；流式细胞仪检测 OSI －906对细胞周期的影响；细胞克隆形成实验分析 OSI －906对 X 线照射敏感性的作用；激光共聚焦观察 OSI －906对 X 线照射 SUNE －1细胞 DNA 断裂的影响。结果：OSI －906明显抑制 SUNE －1细胞增殖；IR 可以激活 IGF －1R／AKT 和 IGF －1R／ERK 信号通路，而OSI －906可以抑制 IGF －1R／AKT 和 PI3K／ERK 信号通路激活；细胞周期分析显示，OSI －906可以增加细胞G2／M期比例；克隆形成实验提示 OSI －906提高 IR 对细胞的放射敏感性；焦点成型实验提示 OSI －906增加X 线照射细胞的γ－H2AX 焦点数。结论：OSI －906增加鼻咽癌细胞放疗敏感性，其机制可能与抑制 PI3K／AKT 和 Ras／MAPK 细胞增殖信号通路激活，改变细胞周期，诱导基因组不稳定性有关。

IGF -1R inhibitor OSI -906 increases radiosensitivity in human nasopharyngeal carcino-ma cell line SUNE -1

Objective:To explore the mechanism of tyrosine kinase inhibitor (TKI)OSI -906 enhance the radio-sensitivity in nasopharyngeal carcinoma cell line.Methods:We examined the effect of OSI -906 on cell proliferation. Then,the activation of AKT and ERK1 /2 which were downstream of IGF -1R,detected after X -ray irradiation and OSI -906 addition by Western blot.The cellcycle was examined by flow cytometry.The survival fraction of SUNE -1 wasmeasured by clonogenic assay.Finally,γ-H2AX assay was used to demonstrate OSI -906 induced genomic insta-bility in SUNE -1 cells.Results:OSI -906,significantly suppressed SUNE -1 cell proliferation.X -ray radiation can activate IGF -1R/AKT and IGF -1R/ERK signaling pathways,but both IGF -1R/AKT and IGF -1R/ERK sig-naling pathways were suppressed by OSI -906.OSI -906 induced SUNE -1 cell cycle arrest in G2 /M phase.The combination of irradiation and OSI -906 apparently inhibited SUNE -1 survival ratio than irradiation alone.In addi-tion,OSI -906 treatment increased γ-H2AX foci that induced by irradiation.Conclusion:OSI -906,pIGF -1R TKI,inactives the downstream protein pAKT and pMAPK,inhibits the proliferation of cells,changes the cell cycle and induced genome instability that might be the potential mechanism to enhance the radiosensitivity in NPC cells.