title: Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells.
abstract: Malignant melanoma is the leading cause of death from skin cancer. 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 δ-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. δ-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, δ-TT exerted its antitumor effect through activation of the PERK/p-eIF2α/ATF4/CHOP, IRE1α and caspase-4 ER stress-related branches. Salubrinal, an inhibitor of the ER stress, counteracted the cytotoxic activity of δ-TT. In vivo experiments performed in nude mice bearing A375 xenografts evidenced that δ-TT reduces tumor volume and tumor mass; importantly, tumor progression was significantly delayed by δ-TT treatment. In conclusion, δ-TT exerts a proapoptotic activity on melanoma cells, through activation of the ER stress-related pathways. δ-TT might represent an effective option for novel chemopreventive/therapeutic strategies for melanoma.
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, 20133, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Montagnani Marelli
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, 20133, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Marzagalli
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, 20133, Italy.
authors.forename: Roberta M
authors.initials: RM
authors.lastname: Moretti
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, Milano, 20133, Italy.
authors.forename: Giangiacomo
authors.initials: G
authors.lastname: Beretta
authors.affiliation: Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Milano, 20129, Italy.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Casati
authors.affiliation: Council for Agricultural Research and Economics, Food and Nutrition Research Centre, Roma, 00178, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Comitato
authors.affiliation: Department of Applied and Biotechnological Clinical Sciences, Università degli Studi dell'Aquila, L'Aquila, 67100, Italy.
authors.forename: Giovanni L
authors.initials: GL
authors.lastname: Gravina
authors.affiliation: Department of Applied and Biotechnological Clinical Sciences, Università degli Studi dell'Aquila, L'Aquila, 67100, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Festuccia
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, 20133, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Limonta
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008819:Mice, Nude; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000096142:Cutaneous Malignant Melanoma
chemical_list: D000970:Antineoplastic Agents; D014810:Vitamin E; C082097:tocotrienol, delta