title: Tivantinib induces G2/M arrest and apoptosis by disrupting tubulin polymerization in hepatocellular carcinoma.
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.
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China. xiangqf171@163.com.|Department of Hepatopancreatobiliary Surgery, The First People's Hospital of Foshan, Foshan, 528000, China. xiangqf171@163.com.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Xiang
authors.affiliation: Department of Hepatopancreatobiliary Surgery, The First People's Hospital of Foshan, Foshan, 528000, China. zzjun@fsyyy.com.
authors.forename: Zuojun
authors.initials: Z
authors.lastname: Zhen
authors.affiliation: Research Center of Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. dengyub@mail.sysu.edu.cn.
authors.forename: David Yb
authors.initials: DY
authors.lastname: Deng
authors.affiliation: Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. wangjn333@mail2.sysu.edu.cn.
authors.forename: Jingnan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Hepatopancreatobiliary Surgery, The First People's Hospital of Foshan, Foshan, 528000, China. 2388379545@qq.com.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Hepatopancreatobiliary Surgery, The First People's Hospital of Foshan, Foshan, 528000, China. highlight_feeling@163.com.
authors.forename: Jieyuan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hepatopancreatobiliary Surgery, The First People's Hospital of Foshan, Foshan, 528000, China. gzcatman@sina.com.
authors.forename: Yingfei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Hepatopancreatobiliary Surgery, The First People's Hospital of Foshan, Foshan, 528000, China. 503257146@qq.com.
authors.forename: Fengjie
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. cnn19900712@126.com.
authors.forename: Ningning
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Hepatopancreatobiliary Surgery, The First People's Hospital of Foshan, Foshan, 528000, China. chwei_fsyyy@163.com.
authors.forename: Huanwei
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China. cyj0509@126.com.
authors.forename: Yajin
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008870:Microtubules / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics; D011760:Pyrrolidinones / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D014404:Tubulin / Q000096:biosynthesis*; D050257:Tubulin Modulators / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C551661:ARQ 197; D000970:Antineoplastic Agents; D011760:Pyrrolidinones; D011804:Quinolines; D034741:RNA, Small Interfering; D014404:Tubulin; D050257:Tubulin Modulators; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met