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.
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