δ-Tocotrienol re-sensitizes vemurafenib-resistant melanoma cells to BRAF inhibition via modulation of AKT signaling.

Melanoma is a highly aggressive skin cancer, with mortality largely driven by the development of resistance to BRAF-targeted therapies such as vemurafenib. Although several combination strategies have been explored, durable responses in resistant disease remain limited, highlighting the need for new therapeutic approaches. δ-tocotrienol (δ-TT), a member of the vitamin E family, has shown anticancer activity in different tumor models, but its effects in BRAF inhibitor-resistant melanoma remain poorly characterized, particularly in the context of acquired resistance and combination treatment strategies. In this study, we investigated the antitumor activity of δ-TT and its ability to restore sensitivity to vemurafenib in resistant melanoma models. To this end, two human melanoma cell lines with acquired resistance (A375R and SK-MEL-28R) were treated with δ-TT alone or in combination with vemurafenib. δ-TT significantly reduced cell viability and clonogenic potential, inducing G1/S cell cycle arrest via downregulation of cyclin D1/D3 and upregulation of p21. It also triggered mitochondrial apoptosis, as indicated by loss of mitochondrial membrane potential, increased Bax/Bcl-2 ratio, cytochrome c release, and activation of caspase-3 and PARP cleavage. In addition, δ-TT impaired migration and invasion by decreasing MMP-2 expression and secretion. These effects were associated with inhibition of AKT signaling. Notably, δ-TT restored responsiveness to vemurafenib, indicating a synergistic interaction in resistant melanoma cells. Overall, these findings provide mechanistic evidence supporting a potential role for δ-TT as a modulator of drug response and support further investigation of δ-TT-based combination strategies to overcome therapeutic resistance in melanoma.