Journal Article

Anthocyanidins inhibit activator protein 1 activity and cell transformation: structure–activity relationship and molecular mechanisms

De-Xing Hou, Keiko Kai, Jian-Jian Li, Shigang Lin, Norihiko Terahara, Mika Wakamatsu, Makoto Fujii, Mattew R. Young and Nancy Colburn

in Carcinogenesis

Volume 25, issue 1, pages 29-36
Published in print January 2004 | ISSN: 0143-3334
Published online January 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg184
Anthocyanidins inhibit activator protein 1 activity and cell transformation: structure–activity relationship and molecular mechanisms

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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.

Keywords: AP-1, activator protein-1; ERK, extracellular signal-regulated kinase; FBS, fetal bovine serum; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; P+, promotion-sensitive; RO, reactive oxygen; SAPK, stress-activated protein kinase; SEK, SAPK/ERK kinase; SOD, superoxide dismutase; TPA, 12-O-tetradecanoylphorbol-13-acetate

Journal Article.  6204 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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