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.