Novel multiple tyrosine kinase inhibitor ponatinib inhibits bFGF-activated signaling in neuroblastoma cells and suppresses neuroblastoma growth in vivo.
Novel multiple tyrosine kinase inhibitor ponatinib inhibits bFGF-activated signaling in neuroblastoma cells and suppresses neuroblastoma growth in vivo.
复制标题
DOI：
10.18632/oncotarget.11580
复制
发表时间：
2017-01-24
期刊：
影响因子：
--
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Li H;Wang Y;Chen Z;Lu J;Pan J;Yu Y;Zhao Y;Zhang H;Hu T;Liu Q;Yang J
神经母细胞瘤是儿童最常见的恶性肿瘤之一。受体酪氨酸激酶的异常激活有助于NB的病理发展。因此，以酪氨酸激酶受体为靶点治疗NB是一个很有前途的策略。在这里，我们报告了一种多靶点酪氨酸激酶抑制剂泊那替尼以剂量依赖性方式抑制NB细胞增殖并诱导NB细胞凋亡。此外，泊那替尼抑制NB细胞的殖民地形成能力。在机制上，泊那替尼有效抑制FGFR 1激活的信号通路。泊那替尼还增强了阿霉素对NB细胞的细胞毒性作用。此外，泊那替尼通过抑制原位异种移植物NB小鼠模型中的肿瘤生长而证明了体内抗肿瘤疗效。总之，我们的结果表明，泊那替尼在体外和体内均抑制NB生长。
Neuroblastoma (NB) is one of the most common pediatric malignancies in children. Abnormal activation of receptor tyrosine kinases contributes to the pathological development of NB. Therefore, targeting tyrosine kinase receptors to cure NB is a promising strategy. Here, we report that a multi-targeted tyrosine kinase inhibitor ponatinib inhibited NB cell proliferation and induced NB cell apoptosis in a dose-dependent manner. In addition, ponatinib suppressed the colony formation ability of NB cells. Mechanistically, ponatinib effectively inhibited the FGFR1-activated signaling pathway. Ponatinib also enhanced the cytotoxic effects of doxorubicin on NB cells. Furthermore, ponatinib demonstrated anti-tumor efficacy in vivo by inhibiting tumor growth in an orthotopic xenograft NB mouse model. In summary, our results showed that ponatinib inhibited NB growth both in vitro and in vivo.