Tivantinib induces G2/M arrest and apoptosis by disrupting tubulin polymerization in hepatocellular carcinoma.
Tivantinib induces G2/M arrest and apoptosis by disrupting tubulin polymerization in hepatocellular carcinoma.
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蒂凡替尼通过破坏肝细胞癌中的微管蛋白聚合来诱导 G2/M 期阻滞和细胞凋亡
DOI：
10.1186/s13046-015-0238-2
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发表时间：
2015-10-12
期刊：
影响因子：
--
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Xiang Q;Zhen Z;Deng DY;Wang J;Chen Y;Li J;Zhang Y;Wang F;Chen N;Chen H;Chen Y
维拉替尼被描述为一种高选择性的MET抑制剂，目前正处于治疗肝细胞癌(HCC)的III期临床试验。然而，最近的研究对维拉替尼的抗肿瘤作用机制提出了质疑。我们发现，维拉替尼不分青红皂白地抑制MET依赖和非依赖的肝癌细胞的增殖。相比之下，其他MET抑制剂JNJ-38877605和PHA-665752仅特异性地抑制MET依赖的肝癌细胞的生长。维拉替尼既不能抑制肝癌细胞中组成性MET的磷酸化，也不能抑制HGF诱导的MET磷酸化。在微管聚合分析中，维坦替尼通过作为微管解聚剂的机制影响微管动力学。有趣的是，与其他微管靶向药物紫杉醇和长春新碱不同，施坦替尼在亲代细胞和多药耐药细胞中显示出类似的抗增殖活性。进一步的研究表明，维拉替尼通过内源性和外源性途径诱导细胞发生G2/M期阻滞，促进细胞凋亡。体内药效评价表明，维拉替尼具有良好的抗肿瘤生长活性，具有抗增殖和促凋亡作用。维拉替尼在肝癌中的抗肿瘤作用是通过靶向微管实现的。不应根据MET状态选择CTANTINB治疗肝细胞癌患者。
Tivantinib has been described as a highly selective inhibitor of MET and is currently in a phase III clinical trial for the treatment of hepatocellular carcinoma (HCC). However, the mechanism of tivantinib anti-tumor effect has been questioned by recent studies. We show that tivantinib indiscriminately inhibited MET dependent and independent HCC cells proliferation. In contrast, other MET inhibitors, JNJ-38877605 and PHA-665752, just specifically inhibited the growth of MET dependent HCC cells. Tivantinib neither inhibit constitutive MET phosphorylation nor HGF-induced MET phosphorylation in HCC cells. In the microtubule polymerization analysis, tivantinib affected microtubule dynamics by a mechanism as a microtubule depolymerizer. Interesting, unlike other microtubule-targeting agents, paclitaxel and vincristine, tivantinib showed similar anti-proliferative activity in parental and multidrug-resistant cells. Further studies demonstrated that tivantinib induced a G2/M arrest and promoted apoptosis by both intrinsic and extrinsic pathway. The in vivo efficacy evaluation showed that tivantinib exhibited a good anti-tumor growth activity with anti-proliferative and pro-apoptotic effects. The potent anti-tumor activity of tivantinib in HCC was achieved by targeting microtubule. Tivantinib treatment for patients with HCC should not be selected based on MET status.