Integrin αVβ3 antagonist Cilengitide enhances efficacy of radiotherapy in endothelial cell and non-small-cell lung cancer models
Integrin αVβ3 antagonist Cilengitide enhances efficacy of radiotherapy in endothelial cell and non-small-cell lung cancer models
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DOI：
10.1016/j.ijrobp.2006.04.036
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发表时间：
2006-08-01
影响因子：
7
通讯作者：
Bo Lu
中科院分区：
文献类型：
--
作者：
Albert, Jeffrey M.;Cao, Carolyn;Bo Lu
目的：整合素 alpha(v)beta(3) 和 alpha(v)beta(5) 在肿瘤生长和血管生成中很重要，最近已被探索作为癌症治疗的靶点。放射治疗还抑制肿瘤生长并影响脉管系统。我们探索了整合素拮抗剂西仑吉肽 (EMD 121974) 与电离辐射的组合。方法和材料：使用 FACS 分析和免疫荧光成像测定人脐静脉内皮细胞 (HUVEC) 以及 H157 和 H460 人非小细胞肺癌细胞的 α(v)β(3) 水平。克隆形成测定、Western 免疫印迹检测裂解的 caspase 3 和膜联蛋白-V 检测用于评估细胞存活和凋亡。采用细胞脱离实验和基质胶实验进一步检验治疗效果。结果：人脐静脉内皮细胞的α(v)β(3)水平最高，其次是H157和H460。有趣的是，我们发现5 Gy 照射诱导所有细胞系中α(v)β(3) 的表达。克隆形成试验显示西仑吉肽具有放射增敏作用，剂量增强比的计算表明，该效果在 HUVEC 中最高（1.38），其次是 H157（1.19）和 H460（1.10），与靶标表达水平相对应。西仑吉肽和放射联合治疗后凋亡细胞增加，西仑吉肽治疗后脱落细胞增加。此外，联合治疗后内皮小管形成减少。结论：我们得出的结论是，辐射在内皮癌和非小细胞肺癌模型中诱导α(v)β(3)整合素表达，整合素拮抗剂西仑吉肽是一种放射增敏剂，与目标整合素表达水平成正比。 (c) 2006 爱思唯尔公司
Purpose: Integrins alpha(v)beta(3) and alpha(v)beta(5) are important in tumor growth and angiogenesis and have been recently explored as targets for cancer therapy. Radiotherapy also inhibits tumor growth and affects vasculature. We explored the combination of integrin antagonist Cilengitide (EMD 121974) and ionizing radiation.Methods and Materials: Levels of alpha(v)beta(3) were determined for human umbilical vein endothelial cells (HUVEC), as well as H157 and H460 human non-small-cell lung cancer cells, using FACS analysis and immunofluorescence imaging. Clonogenic assays, Western immunoblots probed for cleaved caspase 3, and Annexin-V probing were used to evaluate cell survival and apoptosis. A cell detachment assay and matrigel assay were used to further examine the effects of treatment.Results: Human umbilical vein endothelial cells had the highest alpha(v)beta(3) level, followed by H157, and H460. Interestingly, we found that 5 Gy irradiation induced expression of alpha(v)beta(3) in all cell lines. Clonogenic assays showed a radiosensitizing effect with Cilengitide, and calculation of the dose enhancement ratio showed that the effect was highest in HUVECs (1.38), followed by H157 (1.19), and H460 (1.10), corresponding to the levels of target expression. There was an increase in apoptotic cells after combination treatment with Cilengitide and radiation, and there was an increase in detached cells after treatment with Cilengitide. Additionally, there was decreased endothelial tubule formation after combination treatment.Conclusions: We conclude that radiation induces expression of alpha(v)beta(3) integrin in endothelial and non-small-cell lung cancer models, and that integrin antagonist Cilengitide is a radiosensitizer in proportion to the levels of target integrin expression. (c) 2006 Elsevier Inc.