Association between pterostilbene and quercetin inhibits metastatic activity of B16 melanoma.
Inhibition of cancer growth by resveratrol (trans-3,5,4'-trihydroxystilbene; RESV), a phytoalexin present in many plant species, is limited by its low bioavailability. Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene; PTER) and quercetin (3,3',4',5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols, show longer half-life in vivo. In vitro growth of highly malignant B16 melanoma F10 cells (B16M-F10) is inhibited (56%) by short-time exposure (60 min/day) to PTER (40 microm) and QUER (20 microm) (approximate mean values of plasma concentrations measured within the first hour after intravenous administration of 20 mg/kg each polyphenol). Intravenous administration of PTER and QUER (20 mg/kg per day) to mice inhibits (73%) metastatic growth of B16M-F10 cell in the liver, a common site for metastasis development. The anti-metastatic mechanism involves: 1) a PTER-induced inhibition of vascular adhesion molecule 1 expression in the hepatic sinusoidal endothelium, which consequently decreases B16M-F10 cell adhesion to the endothelium through very late activation antigen 4; and 2) a QUER- and PTER-induced inhibition of Bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. Our findings demonstrate that the association of PTER and QUER inhibits metastatic melanoma growth and extends host survival.
Ferrer
Paula
P
Department of Physiology, University of Valencia, Spain.
Asensi
Miguel
M
Segarra
Ramón
R
Ortega
Angel
A
Benlloch
María
M
Obrador
Elena
E
Varea
María T
MT
Asensio
Gregorio
G
Jordá
Leonardo
L
Estrela
José M
JM
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D039041:Integrin alpha4beta1 / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010636:Phenols / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2; D011794:Quercetin / Q000627:therapeutic use*; D013267:Stilbenes / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D039041:Integrin alpha4beta1; D009566:Nitrates; D009573:Nitrites; D010636:Phenols; D019253:Proto-Oncogene Proteins c-bcl-2; D013267:Stilbenes; D019010:Vascular Cell Adhesion Molecule-1; C107773:pterostilbene; D011794:Quercetin; D006861:Hydrogen Peroxide
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