Flavonoids inhibit melanoma lung metastasis by impairing tumor cells endothelium interactions.
Flavonoids comprise a class of low molecular weight compounds displaying a variety of biological activities including inhibition of tumor growth and metastasis. To gain insight into the mechanisms underlying metastasis inhibition, we have employed the B16-BL6 murine melanoma metastasis model. B57BL/6N mice were injected i.v. with tumor cells and Apigenin, Quercetin, or Tamoxifen, each at 50 mg/kg given i.p., and lung tumor cell colonies counted 14-6 days thereafter. Three different injection schedules were used for each drug: (a) daily injection, starting 24 h before injection of the tumor cells; (b) single dose, 24 h preceding tumor challenge; (c) daily injection, starting 24 h after the injection of the tumor cells. All three compounds significantly reduced tumor lung deposits (Apigenin = Quercetin > Tamoxifen). However, when treatment was delayed by 24 h after tumor cells (schedule c), multiple daily doses of Apigenin or Quercetin were less effective that a single dose of the same compound given 24 h before tumor challenge (schedule b). Apigenin and Quercetin, but not Tamoxifen, were found to inhibit VCAM-1 expression in a dose-dependent manner in HUVEC and in murine pulmonary endothelial cells. In ex vivo experiments, the number of tumor cells adhering to lung vessels was significantly diminished in animals treated with a single dose of Apigenin and Quercetin. These findings indicate that the inhibition of tumor cell metastasis by Apigenin or Quercetin may significantly depend on the ability of these compounds to alter the host's microenvironment, further substantiating the role of the intravascular processes in the metastatic cascade.
Piantelli
Mauro
M
Department of Oncology and Neurosciences, G.d'Annunzio University of Chieti-Pescara, Chieti, Italy. mpiantel@unich.it
Rossi
Cosmo
C
Iezzi
Manuela
M
La Sorda
Rossana
R
Iacobelli
Stefano
S
Alberti
Saverio
S
Natali
Pier Giorgio
PG
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D047310:Apigenin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D001202:Ascitic Fluid / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005419:Flavonoids / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011794:Quercetin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D018931:Antineoplastic Agents, Hormonal; D005419:Flavonoids; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D013629:Tamoxifen; D047310:Apigenin; D011794:Quercetin