Tivantinib induces G2/M arrest and apoptosis by disrupting tubulin polymerization in hepatocellular carcinoma. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Xiang, Qingfeng; Zhen, Zuojun; Deng, David; Wang, Jingnan; Chen, Yingjun; Li, Jieyuan; Zhang, Yingfei; Wang, Fengjie; Chen, Ningning; Chen, Huanwei; Chen, Yajin
• Is Part Of: Journal of experimental & clinical cancer research. Volume 34:Issue 1(2015)
• Page Start: 1
• Page End: 13
• Publication Date: 2015-12
• Subjects: Tivantinib -- Hepatocellular carcinoma -- MET -- Cell cycle -- Apoptosis; Cancer -- Periodicals; 616.994005
• DOI: 10.1186/s13046-015-0238-2
• Languages: English
• ISSNs: 1756-9966

Abstract

Abstract Background 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. Results 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. Thein vivo efficacy evaluation showed that tivantinib exhibited a good anti-tumor growth activity with anti-proliferative and pro-apoptotic effects. Conclusions 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.