title: Inhibition of tumor progression by oral piceatannol in mouse 4T1 mammary cancer is associated with decreased angiogenesis and macrophage infiltration.
abstract: 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.
authors: Department of Food Science and Nutrition, Hallym University, Chuncheon, 200-702, South Korea.
authors: Hyerim
authors: H
authors: Song
authors: Department of Food Science and Nutrition, Hallym University, Chuncheon, 200-702, South Korea.
authors: Jae In
authors: JI
authors: Jung
authors: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921, South Korea.
authors: Han Jin
authors: HJ
authors: Cho
authors: Division of Bio-Imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon, 200-701, South Korea.
authors: Song
authors: S
authors: Her
authors: Division of Bio-Imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon, 200-701, South Korea.
authors: Seung-Hae
authors: SH
authors: Kwon
authors: Department of Food Science and Nutrition, University of Ulsan, Ulsan, 680-749, South Korea.
authors: Rina
authors: R
authors: Yu
authors: Department of Food Science and Nutrition, Hallym University, Chuncheon, 200-702, South Korea.
authors: Young-Hee
authors: YH
authors: Kang
authors: WCU Biomodulation Major, Department of Agricultural Biotechnology and Center for Food and Bioconvergence, Seoul National University, Seoul 151-921, South Korea; Advanced Institutes of Convergence Technology, Seoul National University, Suwon, 443-270, South Korea.
authors: Ki Won
authors: KW
authors: Lee
authors: Department of Food Science and Nutrition, Hallym University, Chuncheon, 200-702, South Korea; Advanced Institutes of Convergence Technology, Seoul National University, Suwon, 443-270, South Korea. Electronic address: jyoon@hallym.ac.kr.
authors: Jung Han Yoon
authors: JH
authors: Park
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013267:Stilbenes / Q000008:administration & dosage* / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C498144:Rela protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013267:Stilbenes; D051996:Transcription Factor RelA; C041525:3,3',4,5'-tetrahydroxystilbene
keywords: Breast cancer; Cytokines; MCP-1; Macrophages; Piceatannol; Tumor angiogenesis