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Drug toxicity and resistance represent a serious challange for melanoma treatments. Evidence demonstrates that natural compounds may play a crucial role in cancer prevention, growth and progression. Vitamin E tocotrienols (TT) were shown to possess antitumor activity. Here, we analyzed the effects of \u03b4-TT on melanoma cell growth and the involvement of the endoplasmic reticulum (ER) stress in this activity. The experiments were performed on human melanoma cell lines, BLM and A375. \u03b4-TT exerted a significant proapoptotic effect on both cell lines, involving the intrinsic apoptosis pathway; importantly, this compound did not affect the viability of normal human melanocytes. In melanoma cells, \u03b4-TT exerted its antitumor effect through activation of the PERK\/p-eIF2\u03b1\/ATF4\/CHOP, IRE1\u03b1 and caspase-4 ER stress-related branches. Salubrinal, an inhibitor of the ER stress, counteracted the cytotoxic activity of \u03b4-TT. <jats:italic>In vivo<\/jats:italic> experiments performed in nude mice bearing A375 xenografts evidenced that \u03b4-TT reduces tumor volume and tumor mass; importantly, tumor progression was significantly delayed by \u03b4-TT treatment. In conclusion, \u03b4-TT exerts a proapoptotic activity on melanoma cells, through activation of the ER stress-related pathways. \u03b4-TT might represent an effective option for novel chemopreventive\/therapeutic strategies for melanoma.<\/jats:p>","DOI":"10.1038\/srep30502","type":"journal-article","created":{"date-parts":[[2016,7,27]],"date-time":"2016-07-27T10:11:36Z","timestamp":1469614296000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Vitamin E \u03b4-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells"],"prefix":"10.1038","volume":"6","author":[{"given":"Marina","family":"Montagnani Marelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Marzagalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta M.","family":"Moretti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giangiacomo","family":"Beretta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lavinia","family":"Casati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Comitato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni L.","family":"Gravina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Festuccia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Limonta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,7,27]]},"reference":[{"key":"BFsrep30502_CR1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.jaad.2015.04.014","volume":"73","author":"HW Higgins 2nd","year":"2015","unstructured":"Higgins, H. 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