Tivantinib induces G2/M arrest and apoptosis by disrupting tubulin polymerization in hepatocellular carcinoma

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. © 2015 xiang et al.