Department of Immunology, Harbin Medical University, Harbin 150081, PR China.
Int J Oncol. 2011 Feb;38(2):555-69. doi: 10.3892/ijo.2010.861. Epub 2010 Dec 6.
Clinical studies using the tyrosine kinase inhibitor, imatinib mesylate (Gleevec®), in glioblastoma, have shown no major inhibition of tumor growth or extension of survival for patients, unlike those in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. The molecular mechanisms of action of imatinib in glioblastoma cells are still not well understood. In this study, we investigated the effects of imatinib on the platelet derived growth factor receptor (PDGFR) downstream signaling pathways as well as on other cellular functions in human glioblastoma cells. NIH3T3 fibroblast and K562 CML cells were used for comparison. Western blot analysis demonstrated that imatinib was more effective in inhibiting the activated rather than the quiescent forms of the target proteins. Furthermore, the imatinib treatment induced the sustained activation of extracellular signal-regulated kinase (ERK 1/2) signaling as well as components of other downstream signaling pathways, such as PI3K/Akt, STAT3 and p38MAPK. Prior stimulation of the malignant cells with exogenous PDGF-BB partially abrogated this activation. Further analysis indicated that the activation of ERK induced by the imatinib treatment was related to the S-phase re-entry of the cell cycle in one of the three glioma cells. Imatinib significantly inhibited cell migration but not cell growth. The combination treatment of imatinib with a MEK or PI3K inhibitor resulted in significant growth inhibition but did not inhibit cell migration beyond the inhibition achieved with the imatinib treatment alone. The treatment of glioma cells with small interfering RNA inhibiting PDGFRB, however, evoked enhanced Akt signaling. These results indicate that the imatinib treatment of malignant glioma does not result in significant inhibitory effects and should be used with caution.
临床研究表明，酪氨酸激酶抑制剂甲磺酸伊马替尼（格列卫）在治疗胶质母细胞瘤时，并未像在慢性髓性白血病（CML）和胃肠道间质瘤中那样，显著抑制肿瘤生长或延长患者生存时间。甲磺酸伊马替尼在胶质母细胞瘤细胞中的作用机制尚不清楚。在这项研究中，我们研究了甲磺酸伊马替尼对血小板衍生生长因子受体（PDGFR）下游信号通路以及对人类胶质母细胞瘤细胞其他细胞功能的影响。我们使用 NIH3T3 成纤维细胞和 K562 CML 细胞进行比较。Western blot 分析表明，甲磺酸伊马替尼在抑制靶蛋白的激活形式而非静止形式方面更有效。此外，甲磺酸伊马替尼治疗诱导细胞外信号调节激酶（ERK 1/2）信号以及其他下游信号通路的组成部分（如 PI3K/Akt、STAT3 和 p38MAPK）的持续激活。预先用外源性 PDGF-BB 刺激恶性细胞可部分消除这种激活。进一步分析表明，甲磺酸伊马替尼治疗诱导的 ERK 激活与三种神经胶质瘤细胞中的一种细胞周期 S 期再进入有关。甲磺酸伊马替尼显著抑制细胞迁移，但不抑制细胞生长。甲磺酸伊马替尼与 MEK 或 PI3K 抑制剂联合治疗可显著抑制细胞生长，但不能抑制细胞迁移，其抑制作用不及甲磺酸伊马替尼单独治疗。然而，用抑制 PDGFRB 的小干扰 RNA 处理神经胶质瘤细胞可引起 Akt 信号增强。这些结果表明，甲磺酸伊马替尼治疗恶性神经胶质瘤不会产生显著的抑制作用，应谨慎使用。
