Carboxyamidotriazole Synergizes with Sorafenib to Combat Non-Small Cell Lung Cancer through Inhibition of NANOG and Aggravation of Apoptosis
Carboxyamidotriazole Synergizes with Sorafenib to Combat Non-Small Cell Lung Cancer through Inhibition of NANOG and Aggravation of Apoptosis
复制标题
羧酰胺三唑与索拉非尼协同通过抑制 NANOG 和加剧细胞凋亡来对抗非小细胞肺癌
DOI：
10.1124/jpet.117.240986
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发表时间：
2017-08-01
影响因子：
3.5
通讯作者：
Guo, Lei
中科院分区：
文献类型：
--
作者：
Chen, Chen;Ju, Rui;Guo, Lei
肺癌是目前世界范围内癌症相关死亡的主要原因。在这项研究中，我们研究了羧氨基三唑（CAI）和索拉非尼在非小细胞肺癌（NSCLC）中的体外和体内组合，以测试CAI是否增强索拉非尼的抗肿瘤作用并减少其副作用。联合指数（CI）显示CAI和索拉非尼联合给药可协同抑制NSCLC细胞（刘易斯肺癌、A549和NCI-H1975细胞）的增殖。细胞死亡的组合处理的结果是由于细胞凋亡，这是伴随着激活的半胱天冬酶-3和poly（ADP-核糖）聚合酶。此外，联合治疗诱导了脑组织相关活性氧的积累，以及线粒体的去极化和NANOG（同源框蛋白NANOG）mRNA和蛋白质表达的减少。碱性成纤维细胞生长因子，NANOG的刺激剂，用于确定可能的机制。加入碱性成纤维细胞生长因子，然后进行联合治疗，可以刺激NANOG表达，同时拯救活性氧的积累。将携带刘易斯肺癌的C57 BL/6 J小鼠随机接受载体（聚乙二醇400）、CAI（30 mg/kg）、低剂量索拉非尼（SFB-L; 10 mg/kg）、高剂量索拉非尼（SFB-H; 30 mg/kg）或CAI和SFB-L组合。联合治疗组的肿瘤生长明显受到抑制，联合治疗的疗效与SFB-H单药治疗组相当。此外，与SFB-H组相比，组合组具有减少的副作用，如小鼠体重保持所示。我们的研究表明，CAI增强索拉非尼在NSCLC中的抗肿瘤活性，并为NSCLC的治疗提供了一种新的策略。
Lung cancer is currently the leading cause of cancer-related deaths worldwide. In this study, we investigated the combination of carboxyamidotriazole (CAI) and sorafenib in non-small cell lung cancer (NSCLC) in vitro and in vivo to test whether CAI enhances the antitumor effects of sorafenib and reduces its side effects. The combination index (CI) showed that coadministration of CAI and sorafenib synergistically inhibited the proliferation of NSCLC cells (Lewis lung carcinoma, A549, and NCI-H1975 cells). Cell death as a result of the combination treatment was attributed to apoptosis, which was accompanied by activation of caspase-3 and poly(ADP-ribose) polymerase. In addition, combination therapy induced the accumulation of mitochondrial-associated reactive oxygen species, as well as depolarization of mitochondrial and reduced NANOG (homeobox protein NANOG) mRNA and protein expression. Basic fibroblast growth factor, a stimulator of NANOG, was applied to identify the possible mechanism. The addition of basic fibroblast growth factor followed by combined treatment may stimulate NANOG expression and synchronously rescue the accumulation of reactive oxygen species. C57BL/6J mice bearing Lewis lung carcinoma were randomized to receive vehicle (polyethylene glycol 400), CAI (30 mg/kg), low-dose sorafenib (SFB-L; 10 mg/kg), high-dose sorafenib (SFB-H; 30 mg/kg), or a CAI and SFB-L combination. Tumor growth was significantly suppressed in the combination group, and the efficacy of combination treatment was equivalent to that of the SFB-H monotherapy group. Furthermore, the combination group had reduced side effects compared with the SFB-H group, as indicated by weight preservation in mice. Our study illustrates that CAI enhances the antitumor activity of sorafenib in NSCLC and provides a novel strategy for NSCLC treatment.