Synergistic antitumor effects of dasatinib and oxaliplatin in gastric cancer cells
Synergistic antitumor effects of dasatinib and oxaliplatin in gastric cancer cells
复制标题
DOI：
10.1007/s00280-013-2166-1
复制
发表时间：
2013-07-01
影响因子：
3
通讯作者：
Zhang, Jun
中科院分区：
文献类型：
--
作者：
Shi, Min;Lou, Bingxiang;Zhang, Jun
为探讨Src抑制剂达沙替尼（Dasatinib）与奥沙利铂（Oxaliplatin）对胃癌细胞的协同作用，采用Western blot（WB）法检测10株人胃癌细胞系和胃粘膜上皮细胞系GES-1中总Src和p-Src的基线水平。WB法检测奥沙利铂作用后Src和p-Src表达的变化。采用联合指数法和克隆形成试验评价达沙替尼与奥沙利铂对体外细胞生长和增殖的协同作用。建立了裸小鼠胃癌异种移植瘤，并使用奥沙利铂联合或不联合达沙替尼进行治疗。采用免疫组化染色和WB法检测不同处理对胃癌移植瘤细胞增殖和Src蛋白表达的影响，并计算肿瘤生长曲线。胃癌细胞Src蛋白表达水平的不同与其对奥沙利铂的敏感性不同有关。在体外和体内奥沙利铂暴露后，p-Src的表达升高，但总Src未升高。达沙替尼可显著抑制p-Src表达，联合指标表明达沙替尼和奥沙利铂在抑制胃癌细胞生长方面具有协同作用。在克隆形成试验中，达沙替尼联合奥沙利铂比奥沙利铂或达沙替尼单药治疗更有效地抑制克隆形成。双药治疗组的肿瘤体积和肿瘤重量均显著低于单药治疗组，达沙替尼与奥沙利铂在体内外均能协同抑制胃癌细胞的生长，其作用机制可能是通过抑制奥沙利铂刺激的Src活性而实现的。
The aim of this study is to investigate whether Dasatinib, a Src inhibitor, has the synergistic effect with oxaliplatin in treating gastric cancer cells.The baseline levels of total Src and p-Src in 10 human gastric cancer cell lines and gastric mucosa epithelial cell line GES-1 were detected by Western blot (WB). The changes of Src and p-Src expression after oxaliplatin exposure were evaluated by WB. The combination indices and clonogenic assay were used to evaluate the synergistic effects of dasatinib with oxaliplatin on cell growth and proliferation in vitro. Gastric cancer xenografts in nude mice were established and treated by oxaliplatin with or without dasatinib. The tumor growth curves were calculated and the impacts of different treatment on the tumor proliferation and src protein expression in gastric cancer xenografts were determined by immunohistochemistry staining and WB.The different levels of Src expression in gastric cancer cells were related with their different sensitivity to oxaliplatin. The expression of p-Src, but not total Src, was elevated after oxaliplatin exposure both in vitro and in vivo. Dasatinib could dramatically inhibit p-Src expression, and combination indices demonstrated that dasatinib and oxaliplatin were synergistic in inhibiting gastric cancer cell growth. Dasatinib plus oxaliplatin were more effective in inhibiting clone formation than oxaliplatin or dasatinib monotherapy in clonogenic assay. The tumor volume and tumor weight of xenografts were significantly lower in doublet treatment group than those in single-agent treatment groups.Dasatinib plays synergistic role with oxaliplatin in inhibiting gastric cancer cell growth both in vitro and in vivo, via inhibiting Src activity stimulated by oxaliplatin.