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Tivantinib (ARQ 197) exhibits antitumor activity by directly interacting with tubulin and overcomes ABC transporter-mediated drug resistance.

Molecular cancer therapeutics (2014-10-15)
Aki Aoyama, Ryohei Katayama, Tomoko Oh-Hara, Shigeo Sato, Yasushi Okuno, Naoya Fujita
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Colchicine, BioReagent, suitable for plant cell culture, ≥95% (HPLC)
Sigma-Aldrich
Colchicine, ≥95% (HPLC), powder
Colchicine, (European Pharmacopoeia (EP) Reference Standard)
Sigma-Aldrich
Yttrium, chips, 99.9% trace rare earth metals basis
Sigma-Aldrich
Yttrium, powder, −40 mesh, 99.5% trace rare earth metals basis
Sigma-Aldrich
Yttrium, ingot, 99.9% trace rare earth metals basis
Yttrium, wire reel, 0.1m, diameter 1.0mm, 99.9%
Yttrium, wire reel, 0.05m, diameter 0.5mm, 99.9%
Yttrium, wire reel, 0.05m, diameter 1.0mm, 99.9%
Yttrium, wire reel, 0.05m, diameter 1.0mm, square section, 99.9%
Yttrium, wire reel, 0.1m, diameter 0.5mm, 99.9%
Yttrium, wire reel, 0.2m, diameter 0.5mm, 99.9%
Sigma-Aldrich
Yttrium sputtering target, diam. × thickness 2.00 in. × 0.25 in., 99.9% trace metals basis
Yttrium, wire reel, 0.2m, diameter 1.0mm, 99.9%
Yttrium, rod, 50mm, diameter 12.5mm, cast, 99%
Yttrium, rod, 100mm, diameter 6.35mm, cast, 99%
Yttrium, rod, 50mm, diameter 2.0mm, cast, 99%
Yttrium, rod, 50mm, diameter 6.35mm, cast, 99%
Yttrium, foil, not light tested, 50x50mm, thickness 0.025mm, as rolled, 99%
Yttrium, foil, 25x25mm, thickness 0.125mm, as rolled, 99%
Yttrium, foil, 25x25mm, thickness 0.15mm, as rolled, 99%
Yttrium, foil, 25mm disks, thickness 0.50mm, as rolled, 99%
Yttrium, foil, 50x50mm, thickness 0.125mm, as rolled, 99%
Yttrium, foil, 50x50mm, thickness 0.15mm, as rolled, 99%
Yttrium, foil, not light tested, 25x25mm, thickness 0.005mm, as rolled, 99%
Yttrium, foil, not light tested, 100x100mm, thickness 0.025mm, as rolled, 99%
Yttrium, rod, 100mm, diameter 12.5mm, cast, 99%
Yttrium, foil, not light tested, 25x25mm, thickness 0.025mm, as rolled, 99%