title: Sub-apoptotic dosages of pro-oxidant vitamin cocktails sensitize human melanoma cells to NK cell lysis.
abstract: Alpha-tocopheryl succinate (αTOS), vitamin K3 (VK3) and vitamin C (ascorbic acid, AA) were previously shown to synergistically promote different death pathways in carcinoma cells, depending on their concentrations and combinations. Similar effects were observed herein in melanoma cells, although αTOS behaved as an antagonist. Interestingly, suboptimal cell death-inducing concentrations (1.5 μM αTOS/20 μM AA/0.2 μM VK3) effectively up-regulated activating Natural Killer (NK) cell ligands, including MICA (the stress-signaling ligand of the NKG2D receptor), and/or the ligands of at least one of the natural cytotoxicity receptors (NKp30, NKp44 and NKp46) in 5/6 melanoma cell lines. Only an isolated MICA down-regulation was seen. HLA class I, HLA class II, ULBP1, ULBP2, ULBP3, Nectin-2, and PVR displayed little, if any, change in expression. Ligand up-regulation resulted in improved lysis by polyclonal NK cells armed with the corresponding activating receptors. These results provide the first evidence for concerted induction of cell death by cell-autonomous and extrinsic (immune) mechanisms. Alarming the immune system much below the cell damage threshold may have evolved as a sensitive readout of neoplastic transformation and oxidative stress. Cocktails of vitamin analogues at slightly supra-physiological dosages may find application as mild complements of melanoma treatment, and in chemoprevention.
authors.affiliation: Laboratory of Immunology, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Tremante
authors.affiliation: Department of Clinical and Molecular Sciences, Polytechnic University of Marche, 60020 Ancona, Italy.
authors.forename: Lory
authors.initials: L
authors.lastname: Santarelli
authors.affiliation: Laboratory of Immunology, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lo Monaco
authors.affiliation: Laboratory of Immunology, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Sampaoli
authors.affiliation: Laboratory of Immunology, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Ingegnere
authors.affiliation: Center of Excellence on Electronic Systems (ARCES), University of Bologna, 40123 Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Guerrieri
authors.affiliation: Department of Clinical and Molecular Sciences, Polytechnic University of Marche, 60020 Ancona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tomasetti
authors.affiliation: Laboratory of Immunology, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Patrizio
authors.initials: P
authors.lastname: Giacomini
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000494:pharmacology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D024483:Vitamin K 3 / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology*; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D016877:Oxidants; D014815:Vitamins; D024483:Vitamin K 3; D024502:alpha-Tocopherol; D001205:Ascorbic Acid
keywords: NKG2D; Natural Cytotoxicity Receptors (NCR); autoschizis; melanoma; oxidative stress