Carcinogenesis Advance Access originally published online on September 26, 2003
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Carcinogenesis, Vol. 25, No. 1, 29-36,
January 2004
© Oxford University Press; all rights reserved
CANCER BIOLOGY |
Anthocyanidins inhibit activator protein 1 activity and cell transformation: structure–activity relationship and molecular mechanisms
1 Department of Biochemical Science and Technology, Faculty of Agriculture, Kagoshima University, Kagoshima, 890-0065, Japan, 2 Department of Radiation Research, H115 Halper South Building, Beckman Research Institute, City of Hope National Medical Center, 1500 Duarte Road, Duarte, CA 91010-3000, USA, 3 Department of Food Science and Technology, Minami Kyushu University, Miyazaki 884-0003, Japan and 4 Gene Regulation Section, Basic Research Laboratory, National Cancer Institute, Frederick, MD 21702, USA
Anthocyanins are the chemical components that give the intense color to many fruits and vegetables, such as blueberries, red cabbages and purple sweet potatoes. Extensive studies have indicated that anthocyanins have strong antioxidant activities. To investigate the mechanism of anthocyanidins as an anticancer food source, six kinds of anthocyanidins representing the aglycons of most anthocyanins, were used to examine their effects on tumor promotion in mouse JB6 cells, a validated model for screening cancer chemopreventive agents and elucidating the molecular mechanisms. Of the six anthocyanins tested, only those with an ortho-dihydroxyphenyl structure on the B-ring suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell transformation and activator protein-1 transactivation, suggesting that the ortho-dihydroxyphenyl may contribute to the inhibitory action. Delphinidin, but not peonidin, blocked the phosphorylation of protein kinases in the extracellular signal-regulated protein kinase (ERK) pathway at early times and the c-Jun N-terminal kinase (JNK) signaling pathway at later times. p38 kinase was not inhibited by delphinidin. Furthermore, two mitogen-activated protein kinase (MAPK) specific inhibitors (SP600125 for JNK and UO126 for ERK) could specifically block the activation of JNK and ERK and cell transformation. Those results demonstrate that anthocyanidins contribute to the inhibition of tumorigenesis by blocking activation of the MAPK pathway. These findings provide the first molecular basis for the anticarcinogenic action of anthocyanidins.
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