Induction of G1 cell cycle arrest in human umbilical vein endothelial cells by flavone's inhibition of the extracellular signal regulated kinase cascade.
Dietary flavonoids have demonstrated anti-carcinogenic activity in several animal models, but their mechanisms of action have not yet been clearly established. Here, we show that flavone, a parent compound of flavonoids, inhibits the proliferation, migration, and capillary tube formation of human umbilical vein endothelial cells (HUVECs). Flow cytometric analysis showed that flavone arrests the cell cycle progression at G(1) phase in HUVECs. We observed the down-regulation of the hyperphosphorylated form of retinoblastoma gene product and cyclin-dependent kinases 2 and 4 in flavone-treated cells, but it had no affect on the expression of p53 and cyclin-dependent kinase inhibitors p21(CIP/Waf1) and p27(Kip). Flavone almost completely inhibited the activation of extracellular signal regulated kinase 1. The present results suggest that the flavone moiety of flavonoids is required for anti-proliferative activity of flavonoids and that anti-carcinogenic action of flavonoids in vivo was mediated, at least in part, by inhibiting angiogenesis.
Arakaki
Naokatu
N
Pharmceutical Sciences, The University of Tokushima, Shomachi, Tokushima 770-8505, Japan. arakaki@ph.tokushima-u.ac.jp
Toyofuku
Ayako
A
Emoto
Yuka
Y
Nagao
Tomoko
T
Kuramoto
Yoshinori
Y
Shibata
Hirofumi
H
Higuti
Tomihiko
T
D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D047309:Flavones; D005419:Flavonoids / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology*; D016161:Genes, Retinoblastoma / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047309:Flavones; D005419:Flavonoids; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C043562:flavone