Effect of SU11248 on gastrointestinal stromal tumor-T1 cells: Enhancement of growth inhibition via inhibition of 3-kinase/Akt/mammalian target of rapamycin signaling
Effect of SU11248 on gastrointestinal stromal tumor-T1 cells: Enhancement of growth inhibition via inhibition of 3-kinase/Akt/mammalian target of rapamycin signaling
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DOI：
10.1111/j.1349-7006.2006.00263.x
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发表时间：
2006-09-01
期刊：
影响因子：
5.7
通讯作者：
Taguchi, Hirokuni
中科院分区：
文献类型：
--
作者：
Ikezoe, Takayuki;Yang, Yang;Taguchi, Hirokuni
SU 11248是一种口服III型和V型受体酪氨酸激酶抑制剂。临床研究已经显示了SU 11248在胃肠道间质瘤（GIST）患者中的疗效;然而，SU 11248抑制这些肿瘤细胞增殖的分子机制仍有待充分阐明。利用GIST-T1细胞，它具有激活突变的c-KIT基因的外显子11，我们检查了SU 11248在GIST细胞的药用作用。克隆形成和MTT试验表明，SU 11248有效地抑制GIST-T1细胞的增殖，IC 50分别约为1 nM和40 nM。SU 11248（10或20 nM，48 h）激活caspase-3并诱导GIST-T1细胞凋亡，通过caspase测定、膜联蛋白V染色和聚（ADP-核糖）聚合酶裂解测定。Western blot分析发现，SU 11248阻断c-KIT的自磷酸化，并抑制其下游效应子，包括Akt和细胞外信号调节激酶，但不抑制信号转导子和转录激活子。有趣的是，当LY 294002或雷帕霉素同时阻断磷脂酰肌醇3-激酶/Akt/哺乳动物雷帕霉素靶点信号传导时，SU 11248介导的生长抑制作用增强。总之，本研究支持SU 11248用于GIST个体的临床研究，SU 11248与3-激酶/Akt/哺乳动物雷帕霉素靶点信号传导抑制剂的组合代表了一种有前景的新型治疗策略。
SU11248 is an orally available type III and V receptor tyrosine kinase inhibitor. Clinical studies have shown the efficacy of SU11248 in individuals with gastrointestinal stromal tumors (GIST); however, the molecular mechanisms by which SU11248 inhibits the proliferation of these tumor cells remains to be fully elucidated. Taking advantage of GIST-T1 cells, which possess an activating mutation in exon 11 of the c-KIT gene, we examined the medicinal action of SU11248 in GIST cells. Clonogenic and MTT assays showed that SU11248 potently inhibited the proliferation of GIST-T1 cells with IC50 of approximately 1 nM and 40 nM, respectively. SU11248 (10 or 20 nM, 48 h) activated caspase-3 and induced apoptosis of GIST-T1 cells as measured by caspase assay, annexin V staining and cleavage of poly (ADP-ribose) polymerase. Western blot analyses found that SU11248 blocked autophosphorylation of c-KIT in association with inhibition of its downstream effectors, including Akt and extracellular signal-regulated kinase, but not signal transducers and activators of transcription. Interestingly, when phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling was blocked simultaneously by either LY294002 or rapamycin, growth inhibition mediated by SU11248 was potentiated. Taken together, this study supports clinical studies of SU11248 for individuals with GIST, and the combination of SU11248 and inhibitors of 3-kinase/Akt/mammalian target of rapamycin signaling represents a promising novel treatment strategy.