title: Resveratrol prevents inflammation-dependent hepatic melanoma metastasis by inhibiting the secretion and effects of interleukin-18.
abstract: BACKGROUND
  Implantation and growth of metastatic cancer cells at distant organs is promoted by inflammation-dependent mechanisms. A hepatic melanoma metastasis model where a majority of metastases are generated via interleukin-18-dependent mechanisms was used to test whether anti-inflammatory properties of resveratrol can interfere with mechanisms of metastasis.
  
  
  METHODS
  Two experimental treatment schedules were used: 1) Mice received one daily oral dose of 1 mg/kg resveratrol after cancer cell injection and the metastasis number and volume were determined on day 12. 2) Mice received one daily oral dose of 1 mg/kg resveratrol along the 5 days prior to the injection of cancer cells and both interleukin-18 (IL-18) concentration in the hepatic blood and microvascular retention of luciferase-transfected B16M cells were determined on the 18th hour. In vitro, primary cultured hepatic sinusoidal endothelial cells were treated with B16M-conditioned medium to mimic their in vivo activation by tumor-derived factors and the effect of resveratrol on IL-18 secretion, on vascular cell adhesion molecule-1 (VCAM-1) expression and on tumor cell adhesion were studied. The effect of resveratrol on melanoma cell activation by IL-18 was also studied.
  
  
  RESULTS
  Resveratrol remarkably inhibited hepatic retention and metastatic growth of melanoma cells by 50% and 75%, respectively. The mechanism involved IL-18 blockade at three levels: First, resveratrol prevented IL-18 augmentation in the blood of melanoma cell-infiltrated livers. Second, resveratrol inhibited IL-18-dependent expression of VCAM-1 by tumor-activated hepatic sinusoidal endothelium, preventing melanoma cell adhesion to the microvasculature. Third, resveratrol inhibited adhesion- and proliferation-stimulating effects of IL-18 on metastatic melanoma cells through hydrogen peroxide-dependent nuclear factor-kappaB translocation blockade on these cells.
  
  
  CONCLUSIONS
  These results demonstrate multiple sites for therapeutic intervention using resveratrol within the prometastatic microenvironment generated by tumor-induced hepatic IL-18, and suggest a remarkable effect of resveratrol in the prevention of inflammation-dependent melanoma metastasis in the liver.
authors.affiliation: CEU-San Pablo University School of Medicine, Institute of Applied Molecular Medicine, Boadilla del Monte, Madrid, Spain.
authors.forename: Clarisa
authors.initials: C
authors.lastname: Salado
authors.forename: Elvira
authors.initials: E
authors.lastname: Olaso
authors.forename: Natalia
authors.initials: N
authors.lastname: Gallot
authors.forename: Maria
authors.initials: M
authors.lastname: Valcarcel
authors.forename: Eider
authors.initials: E
authors.lastname: Egilegor
authors.forename: Lorea
authors.initials: L
authors.lastname: Mendoza
authors.forename: Fernando
authors.initials: F
authors.lastname: Vidal-Vanaclocha
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000150:complications / Q000517:prevention & control*; D020382:Interleukin-18 / Q000378:metabolism*; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000150:complications / Q000473:pathology*; D008545:Melanoma / Q000150:complications / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D008546:Melanoma, Experimental / Q000150:complications / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D008954:Models, Biological; D009368:Neoplasm Transplantation; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*; D059016:Tumor Microenvironment / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D020382:Interleukin-18; D013267:Stilbenes; D019010:Vascular Cell Adhesion Molecule-1; D000077185:Resveratrol