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Synergistic Activity of the c-Met and Tubulin Inhibitor Tivantinib (ARQ197) with Pemetrexed in Mesothelioma Cells

[ Vol. 15 , Issue. 14 ]

Author(s):

Leticia G. Leon, Maria Gemelli, Rocco Sciarrillo, Amir Avan, Niccola Funel and Elisa Giovannetti   Pages 1331 - 1340 ( 10 )

Abstract:


Malignant pleural mesothelioma (MPM) is a lethal disease with scarce therapeutic options, and preclinical studies on new targeted-agents are warranted. Because previous studies reported high c-Met expression and alterations in the microtubules network in most MPM samples, we evaluated the activity of tivantinib, which has been recently suggested to affect microtubule polymerization in addition to inhibiting c-Met. In four MPM cell lines tivantinib inhibited both c-Met activity and microtubule polymerization, resulting in inhibition of cell-growth with IC50s ranging between 0.3 µM (MSTO-211H) and 2.4 µM (H2052). Furthermore tivantinib synergistically enhanced the antiproliferative and proapoptotic activity of pemetrexed, as detected by sulforhodamine-B-assay and flow cytometry. The synergistic interaction was associated with reduction of thymidylate synthase expression and inhibition of migratory activity. In aggregate, these data show the ability of tivantinib to specifically target key pathways in MPM cells and synergistically interact with pemetrexed, supporting further studies on this therapeutic approach.

Keywords:

c-Met, malignant pleural mesothelioma, migration, pemetrexed, synergistic interaction, tivantinib, tubulin.

Affiliation:

Center for Biomedical Research of the Canary Islands, Instituto de Tecnologias Biomedicas, University of La Laguna, Campus de la Salud s/n, 38071 La Laguna, Tenerife, Spain.



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