Sorafenib sensitizes human colorectal carcinoma to radiation via suppression of NF-κB expression in vitro and in vivo
Sorafenib sensitizes human colorectal carcinoma to radiation via suppression of NF-κB expression in vitro and in vivo
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DOI：
10.1016/j.biopha.2011.09.011
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发表时间：
2012-02-01
影响因子：
7.5
通讯作者：
Hwang, Jeng-Jong
中科院分区：
文献类型：
--
作者：
Kuo, Yu-Cheng;Lin, Wei-Chan;Hwang, Jeng-Jong
在肿瘤放疗后期，常可观察到治疗后残留肿瘤中转录因子核因子-κ B（NF-κ B）的过度表达，导致肿瘤放射抵抗和治疗效果差。在这项研究中，我们联合索拉非尼，多激酶抑制剂，电离辐射的治疗效果进行评估，并阐明可能的机制，负责放射增敏索拉非尼对人HT 29/tk-luc大肠癌在体外和体内。采用克隆存活率和细胞周期分析评价索拉非尼的体外细胞毒性。采用HT 29/tk-luc荷瘤动物模型，从细胞凋亡和肿瘤细胞侵袭两方面研究了NF-κ B的联合作用及其在治疗效果中的作用。采用电泳迁移率变动分析（EMSA）和Western blot检测NF-κ B及其下游相关蛋白的表达。索拉非尼联合放疗对HT 29/tk-luc细胞具有协同的细胞毒作用，并能增加肿瘤细胞凋亡。EMSA和Western blot均显示索拉非尼可显著抑制辐射诱导的NF-κ B活性。索拉非尼与放射线联合应用对肿瘤生长的抑制作用明显优于单独应用索拉非尼或单独应用放射线（P < 0.001）。因此，索拉非尼联合放射治疗人结直肠癌具有协同作用。协同作用的机制是通过抑制辐射诱导的NF-κ B表达及其调控的下游基因产物。(C)2012年Elsevier Masson SAS。All rights reserved.
Over-expression of transcription factor nuclear factor-kappa B (NF-kappa B) in the residual tumor after the treatment is often observed at the later period of cancer radiotherapy, results in tumor radioresistance and poor treatment outcome. In this study, we combined sorafenib, a multikinase inhibitor, with ionizing radiation to evaluate the therapeutic effect, and to elucidate the possible mechanism responsible for the radiosensitization of sorafenib on a human HT29/tk-luc colorectal carcinoma in vitro and in vivo. Clonogenic survival and cell cycle analysis were used to evaluate the cytotoxicity of sorafenib in vitro. The combination effect and the role of NF-kappa B in therapeutic efficacy with respects in apoptosis and tumor cell invasion were studied with HT29/tk-luc tumor-bearing animal model. The expression of NF-kappa B and its downstream-related proteins were assayed with electrophoretic mobility shift assay (EMSA) and Western blot. Sorafenib combined with radiation shows the synergistic cytotoxicity on HT29/tk-luc cells and increased tumor cell apoptosis. Both EMSA and Western blot show that the NF-kappa B activity induced by radiation is significantly suppressed by sorafenib. Combination of sorafenib and radiation shows the maximum tumor growth inhibition as compared to that of sorafenib alone or radiation alone in vivo (P < 0.001). In conclusion, the effect of sorafenib combined with radiation for the treatment of human colorectal carcinoma is synergistic. The mechanism of synergism is through the inhibition of radiation-induced NF-kB expression and its regulated downstream gene products. (C) 2012 Elsevier Masson SAS. All rights reserved.