Malignant mesothelioma (MM) is an aggressive cancer with a poor prognosis. We focused on the anticancer activity of tocotrienol (T3) and previously reported that a novel redox-inactive T3 derivative, 6-O-carboxypropyl-α-tocotrienol (T3E), exhibits stronger inhibitory effects on MM cell growth compared to α-T3 in vitro. Here, we present the underlying mechanisms. First, we identified Yes, a member of the Src family kinases, as a central mediator of MM cell growth and suggested that the Yes/hypoxia-inducible factor-2α (HIF-2α)/vascular endothelial growth factor (VEGF) pathway could be a promising therapeutic target for T3E in MM cells. Second, we investigated the mevalonate pathway and demonstrated that T3E disrupted the activated cap-dependent translation complex through the inactivation of the oncogene Ras. Third, we revealed that T3E targeted the epigenetic induction of Dickkopf-1 (DKK1), a Wnt antagonist, which may lead to an effective treatment of MM. Moreover, T3E suppressed tumor growth in a xenograft model of MM. The area under the plasma concentration-time curve (AUC) from 0 to 24 hours for T3E was twice as high as that for α-T3 in ICR mice. Thus, vitamin E analogs like T3E may have potential anticancer effects.

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