title: Tivantinib (ARQ 197) exhibits antitumor activity by directly interacting with tubulin and overcomes ABC transporter-mediated drug resistance.
abstract: Tivantinib (ARQ197) was first reported as a highly selective inhibitor of c-MET and is currently being investigated in a phase III clinical trial. However, as recently reported by us and another group, tivantinib showed cytotoxic activity independent of cellular c-MET status and also disrupted microtubule dynamics. To investigate if tivantinib exerts its cytotoxic activity by disrupting microtubules, we quantified polymerized tubulin in cells and xenograft tumors after tivantinib treatment. Consistent with our previous report, tivantinib reduced tubulin polymerization in cells and in mouse xenograft tumors in vivo. To determine if tivantinib directly binds to tubulin, we performed an in vitro competition assay. Tivantinib competitively inhibited colchicine but not vincristine or vinblastine binding to purified tubulin. These results imply that tivantinib directly binds to the colchicine binding site of tubulin. To predict the binding mode of tivantinib with tubulin, we performed computer simulation of the docking pose of tivantinib with tubulin using GOLD docking program. Computer simulation predicts tivantinib fitted into the colchicine binding pocket of tubulin without steric hindrance. Furthermore, tivantinib showed similar IC50 values against parental and multidrug-resistant cells. In contrast, other microtubule-targeting drugs, such as vincristine, paclitaxel, and colchicine, could not suppress the growth of cells overexpressing ABC transporters. Moreover, the expression level of ABC transporters did not correlate with the apoptosis-inducing ability of tivantinib different from other microtubule inhibitor. These results suggest that tivantinib can overcome ABC transporter-mediated multidrug-resistant tumor cells and is potentially useful against various tumors.
authors.affiliation: The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Aoyama
authors.affiliation: The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katayama
authors.affiliation: The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Oh-Hara
authors.affiliation: The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Sato
authors.affiliation: Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. naoya.fujita@jfcr.or.jp.
authors.forename: Naoya
authors.initials: N
authors.lastname: Fujita
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C551661:ARQ 197; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D011760:Pyrrolidinones; D011804:Quinolines; D014404:Tubulin; D050257:Tubulin Modulators; D019859:Proto-Oncogene Proteins c-met