Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Key Laboratory of Reproduction and Genetics in Ningxia, Ningxia Medical University, Yinchuan 750004, China.
Sci Rep. 2016 Jul 8;6:29382. doi: 10.1038/srep29382.
Gastric cancer, highly dependent on tumor angiogenesis, causes uncontrolled lethality, in part due to chemoresistance. Here, we demonstrate that linifanib (ABT-869), a novel multi-targeted receptor tyrosine kinase inhibitor, markedly augments cytotoxicity of chemotherapies in human gastric cancer. ABT-869 and chemotherapeutic agents exhibited a strong synergy to inhibit the viability of several gastric cancer cell lines, with combination index values ranging from 0.017 to 0.589. Additionally, the combination of ABT-869 and chemotherapeutic agents led to remarkable suppression of vascular endothelial growth factor (VEGF)-induced angiogenesis in vitro and in vivo. Importantly, in a preclinical gastric cancer xenograft mouse model, drug co-treatments led to increased mouse survival as well as a synergistic reduction in tumor size and the inhibition of tumor angiogenesis. Mechanistic studies further revealed that all of the co-treatments containing ABT-869 resulted in decreased activation of the VEGF receptor, the epidermal growth factor receptor and the insulin growth factor receptor. Inhibition of these receptor tyrosine kinases consequently attenuated the activation of the downstream AKT/mTOR signaling pathway both in cultured gastric cancer cells and in gastric cancer xenografts. Collectively, our findings suggest that the addition of ABT-869 to traditional chemotherapies may be a promising strategy for the treatment of human gastric cancer.
胃癌高度依赖肿瘤血管生成，导致无法控制的致死率，部分原因是化疗耐药。在这里，我们证明了新型多靶点受体酪氨酸激酶抑制剂 linifanib（ABT-869）可显著增强人胃癌对化疗的细胞毒性。ABT-869 和化疗药物对几种胃癌细胞系的活力表现出强烈的协同抑制作用，组合指数值范围从 0.017 到 0.589。此外，ABT-869 与化疗药物的联合使用导致体外和体内血管内皮生长因子（VEGF）诱导的血管生成显著抑制。重要的是，在临床前胃癌异种移植小鼠模型中，药物联合治疗导致小鼠存活率增加，肿瘤体积协同减小，并抑制肿瘤血管生成。机制研究进一步表明，所有包含 ABT-869 的联合治疗均导致 VEGF 受体、表皮生长因子受体和胰岛素生长因子受体的激活减少。这些受体酪氨酸激酶的抑制作用继而减弱了在培养的胃癌细胞和胃癌异种移植中的下游 AKT/mTOR 信号通路的激活。总的来说，我们的研究结果表明，将 ABT-869 加入传统化疗中可能是治疗人类胃癌的一种有前途的策略。
