Piceatannol, a
polyphenol which exhibits anticancer activities, is found in grapes, red wine and berries. It has been shown to inhibit several
transcription factor pathways. The present study was conducted to determine whether
oral administration of
piceatannol inhibits mammary
tumor progression. 4T1 mammary
carcinoma cells were injected into the mammary fat pad of syngeneic female BALB/c mice. Starting 1 day later,
piceatannol (10- or 20-mg/kg
body weight/day) was administered by oral gavage for 30 days.
Piceatannol treatment reduced
tumor growth. In
tumor tissues,
piceatannol treatment reduced the expression of
transcription factors P-NFκB p65, P-STAT3 and HIF-1α and multiple
proteins involved in regulation of cell cycle progression (Ki67,
cyclin D1,
cyclin A, CDK2, CDK4), angiogenesis (VEGF-A, VEGFR-2, VE-cadherin, CD31) and lymphangiogenesis (VEGF-C, LYVE-1), as well as macrophage infiltration.
Piceatannol significantly increased apoptotic cells and expression of both Bax and cleaved
caspase-3 but reduced Bcl-2 expression in
tumor tissues. In addition,
piceatannol reduced the number and volume of pulmonary
tumor nodules and expression of MMP-9 in both lung and
tumor. It also reduced tissue levels of
cytokines/
chemokines, including
M-CSF and MCP-1. In vitro results revealed that
piceatannol inhibited migration of 4T1 cells and monocytes, as well as secretion of MCP-1 and
M-CSF by 4T1 cells. 4T1 cell-
conditioned medium stimulated monocyte migration, which was suppressed by a CCR2 antibody. These results indicate that alteration in tumor microenvironment (macrophages,
transcription factors, etc.) is an important mechanism by which
piceatannol inhibits
tumor proliferation, angiogenesis and lymphangiogenesis, leading to suppression of mammary
tumor growth and
metastasis.