Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress.
Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress.
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DOI：
10.1158/0008-5472.can-08-2246
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发表时间：
2009-05-01
期刊：
影响因子：
11.2
通讯作者：
Gallick GE
中科院分区：
文献类型：
--
作者：
Kopetz S;Lesslie DP;Dallas NA;Park SI;Johnson M;Parikh NU;Kim MP;Abbruzzese JL;Ellis LM;Chandra J;Gallick GE
治疗结直肠癌的化疗方案通常包括奥沙利铂，尽管固有的和获得性的耐药性很常见。奥沙利铂敏感性的一种潜在介质是非受体蛋白酪氨酸激酶 Src，其活性与疾病阶段和患者生存相关。因此，我们研究了使用酪氨酸激酶抑制剂达沙替尼抑制 Src 对奥沙利铂敏感性的影响。我们证明奥沙利铂可急剧激活 Src，并且与达沙替尼的联合治疗以细胞系依赖性方式产生协同作用，Src 激活水平与一组六种细胞系中的协同程度相关。奥沙利铂治疗后细胞内产生活性氧（ROS），ROS有效激活Src。用抗氧化剂预处理可抑制奥沙利铂诱导的 Src 激活。在奥沙利铂耐药细胞系中，Src 活性持续增加。在结直肠肝转移小鼠模型中，奥沙利铂治疗也会导致 Src 慢性激活。与单药治疗相比，达沙替尼和奥沙利铂的组合可显着缩小肿瘤，相应地减少增殖和血管生成。因此，我们得出结论，奥沙利铂通过 ROS 依赖性机制激活 Src。 Src 抑制可增加奥沙利铂的体外和体内活性。这些结果表明，Src 抑制剂与奥沙利铂组合可能对转移性结肠癌有效，并且可能提供对此类组合敏感的分子表型的第一个迹象。
Chemotherapeutic regimens for the treatment of colorectal cancer generally include oxaliplatin, although inherent and acquired resistance is common. One potential mediator of oxaliplatin sensitivity is the non-receptor protein tyrosine kinase, Src, the activity of which correlates with disease stage and patient survival. Therefore, we investigated the effects of Src inhibition using the tyrosine kinase inhibitor dasatinib on oxaliplatin sensitivity. We demonstrate that oxaliplatin acutely activates Src and that combination treatment with dasatinib is synergistic in a cell-line dependent manner, with the level of Src activation correlating with extent of synergy in a panel of six cell lines. Intracellular reactive oxygen species (ROS) are generated after oxaliplatin treatment, and ROS potently activates Src. Pretreatment with antioxidants inhibits oxaliplatin-induced Src activation. In oxaliplatin resistant cell lines, Src activity is constitutively increased. In a mouse model of colorectal liver metastases, treatment with oxaliplatin also results in chronic Src activation. The combination of dasatinib and oxaliplatin results in significantly smaller tumors compared to single agent treatment, corresponding with reduced proliferation and angiogenesis. Therefore, we conclude that oxaliplatin activates Src through a ROS-dependent mechanism. Src inhibition increases oxaliplatin activity both in vitro and in vivo. These results suggest that Src inhibitors combined with oxaliplatin may have efficacy in metastatic colon cancer, and may provide the first indication of a molecular phenotype that might be susceptible to such combinations.