Imatinib inhibits proliferation of Ewing tumor cells mediated by the stem cell Factor/KIT receptor pathway, and sensitizes cells to vincristine and doxorubicin-induced apoptosis
Imatinib inhibits proliferation of Ewing tumor cells mediated by the stem cell Factor/KIT receptor pathway, and sensitizes cells to vincristine and doxorubicin-induced apoptosis
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DOI：
10.1158/1078-0432.ccr-0778-03
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发表时间：
2004-01-15
影响因子：
11.5
通讯作者：
de Alava, E
中科院分区：
文献类型：
--
作者：
Gonz치lez, I;Andreu, EJ;de Alava, E
目的和实验设计：干细胞因子/KIT 受体环可能代表尤文肿瘤分子治疗的新靶点。我们分析了伊马替尼 KIT 阻断对尤文肿瘤细胞系的体外影响。结果：通过免疫组织化学和/或蛋白质印迹分析，在 4 个尤文肿瘤细胞系中的 4 个以及 110 个患者样本中的 49 个样本 (44.5%) 中检测到 KIT 表达。 Ewing 肿瘤中 KIT 表达更强，显示 EWS-FL11 非 1 型融合。尽管不存在 c-kit 突变，但在所有肿瘤细胞系中都发现了 KIT 的组成型和配体诱导型磷酸化，表明存在活性受体。用 KIT 酪氨酸激酶抑制剂伊马替尼 (0.5-20 muM) 治疗可诱导 KIT 磷酸化下调和细胞增殖的剂量反应抑制（IC50，12-15 muM）。然而，以接近抑制生长的IC50（10μM）的剂量单独施用伊马替尼并没有诱导细胞凋亡的显着增加。然后，我们分析了通过伊马替尼 (10 muM) 阻断 KIT 环是否能够增加多柔比星 (DXR) 和长春新碱 (VCR)（通常用于尤文肿瘤治疗的药物）的体外抗肿瘤效果。添加伊马替尼可使暴露于 DXR 和 VCR 的尤文肿瘤细胞的增殖率分别降低 15-20% 和 15-36%，而使暴露于相同药物的尤文肿瘤细胞的凋亡率增加 15% 和 30%。 结论：伊马替尼对尤文肿瘤细胞增殖的抑制是通过阻断 KIT 受体信号介导的。抑制 KIT 会增加这些细胞对 DXR 和 VCR 的敏感性。这项研究支持伊马替尼在治疗尤文瘤中的潜在作用。
Purpose and Experimental Design: The stem cell factor/KIT receptor loop may represent a novel target for molecular-based therapies of Ewing tumor. We analyzed the in vitro impact of KIT blockade by imatinib in Ewing tumor cell lines.Results: KIT expression was detected in 4 of 4 Ewing tumor cell lines and in 49 of 110 patient samples (44.5%) by immunohistochemistry and/or Western blot analysis. KIT expression was stronger in Ewing tumors showing EWS-FL11 nontype 1 fusions. Despite absence of c-kit mutations, constitutive and ligand-inducible phosphorylation of KIT was found in all tumor cell lines, indicating an active receptor. Treatment with KIT tyrosine kinase inhibitor imatinib (0.5-20 muM) induced down-regulation of KIT phosphorylation and dose response inhibition of cell proliferation (IC50, 12-15 muM). However, imatinib administered alone at doses close to IC50 for growth inhibition (10 muM) did not induce a significant increase in apoptosis. We then analyzed if blockade of KIT loop through imatinib (10 muM) was able to increase the antitumor in vitro effect of doxorubicin (DXR) and vincristine (VCR), drugs usually used in Ewing tumor treatment. Addition of imatinib decreased in 15-20 and 15-36% of the proliferative rate of Ewing tumor cells exposed to DXR and VCR, respectively, and increased in 15 and 30% of the apoptotic rate of Ewing tumor cells exposed to the same drugs.Conclusions: Inhibition of Ewing tumor cell proliferation by imatinib is mediated through blockade of KIT receptor signaling. Inhibition of KIT increases sensitivity of these cells to DXR and VCR. This study supports a potential role for imatinib in the treatment of Ewing tumor.