title: d-δ-Tocotrienol-mediated cell cycle arrest and apoptosis in human melanoma cells.
abstract: BACKGROUND
  The rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, provides essential intermediates for the prenylation or dolichylation of growth-related proteins. d-δ-tocotrienol, a post-transcriptional down-regulator of HMG CoA reductase, suppresses the proliferation of murine B16 melanoma cells. Dietary d-δ-tocotrienol suppresses the growth of implanted B16 melanomas without toxicity to host mice.
  
  
  METHODS
  The proliferation of human A2058 and A375 melanoma cells following a 72 h incubation in 96-well plates was measured by CellTiter 96® Aqueous One Solution. Cell cycle distribution was determined by flow cytometry. Fluorescence microscopy following acridine orange and ethidium bromide dual staining and procaspase-3 cleavage were used to detect apoptosis. Western-blot was employed to measure protein expression.
  
  
  RESULTS
  d-δ-Tocotrienol induced dose-dependent suppression of cell proliferation with 50% inhibitory concentrations (IC(50)) of 37.5 ± 1.4 (A2058) and 22.3 ± 1.8 (A375) μmol/l, respectively (data are reported as mean ± standard deviation). d-δ-Tocotrienol-mediated cell cycle arrest at the G(1) phase was accompanied by reduced expression of cyclin-dependent kinase 4. Concomitantly, d-δ-tocotrienol induced caspase-3 activation and apoptosis. The impact of d-δ-tocotrienol on A2058 cell proliferation was potentiated by lovastatin (IC(50)=3.1 ± 0.5 μmol/l), a competitive inhibitor of HMG CoA reductase.
  
  
  CONCLUSIONS
  d-δ-Tocotrienol may have potential application in melanoma chemoprevention and/or therapy.
authors.affiliation: Department of Nutrition and Food Sciences, Texas Woman's University, PO Box 425888, Denton, TX 76204, USA.
authors.forename: Nicolle V
authors.initials: NV
authors.lastname: Fernandes
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Guntipalli
authors.forename: Huanbiao
authors.initials: H
authors.lastname: Mo
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008148:Lovastatin / Q000008:administration & dosage / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology*; D013692:Telophase / Q000187:drug effects; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D014810:Vitamin E; C082097:tocotrienol, delta; D008148:Lovastatin