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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.
AuthorsElisa Tremante, Lory Santarelli, Elisa Lo Monaco, Camilla Sampaoli, Tiziano Ingegnere, Roberto Guerrieri, Marco Tomasetti, Patrizio Giacomini
JournalOncotarget (Oncotarget) Vol. 6 Issue 31 Pg. 31039-49 (Oct 13 2015) ISSN: 1949-2553 [Electronic] United States
PMID26427039 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Oxidants
  • Vitamins
  • Vitamin K 3
  • alpha-Tocopherol
  • Ascorbic Acid
Topics
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Apoptosis (drug effects)
  • Ascorbic Acid (pharmacology)
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic (drug effects)
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Humans
  • Killer Cells, Natural (drug effects, immunology, metabolism)
  • Melanoma (drug therapy, immunology, metabolism, pathology)
  • Oxidants (pharmacology)
  • Oxidative Stress (drug effects)
  • Signal Transduction (drug effects)
  • Skin Neoplasms (drug therapy, immunology, metabolism, pathology)
  • Vitamin K 3 (pharmacology)
  • Vitamins (pharmacology)
  • alpha-Tocopherol (pharmacology)

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