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  • Title: Tivantinib induces G2/M arrest and apoptosis by disrupting tubulin polymerization in hepatocellular carcinoma.
    Author: Xiang Q, Zhen Z, Deng DY, Wang J, Chen Y, Li J, Zhang Y, Wang F, Chen N, Chen H, Chen Y.
    Journal: J Exp Clin Cancer Res; 2015 Oct 12; 34():118. PubMed ID: 26458953.
    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. The in 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.
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