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. • δ-TT triggers G1 phase cell cycle arrest in vemurafenib-resistant melanoma cells. • δ-TT induces mitochondrial apoptosis in vemurafenib-resistant melanoma cells. • δ-TT suppresses tumor cell migration and invasion via MMP-2 downregulation. • δ-TT antitumor activity is associated with AKT inhibition. • δ-TT re-sensitizes vemurafenib-insensitive cancer cells to BRAF inhibition.