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

Anthocyanins are the chemical components that give the intensecolor to many fruits and vegetables, such as blueberries, redcabbages and purple sweet potatoes. Extensive studies have indicatedthat anthocyanins have strong antioxidant activities. To investigatethe mechanism of anthocyanidins as an anticancer food source,six kinds of anthocyanidins representing the aglycons of mostanthocyanins, were used to examine their effects on tumor promotionin mouse JB6 cells, a validated model for screening cancer chemopreventiveagents and elucidating the molecular mechanisms. Of the sixanthocyanins tested, only those with an ortho-dihydroxyphenylstructure 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 tothe inhibitory action. Delphinidin, but not peonidin, blockedthe phosphorylation of protein kinases in the extracellularsignal-regulated protein kinase (ERK) pathway at early timesand the c-Jun N-terminal kinase (JNK) signaling pathway at latertimes. 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 blockthe activation of JNK and ERK and cell transformation. Thoseresults demonstrate that anthocyanidins contribute to the inhibitionof tumorigenesis by blocking activation of the MAPK pathway.These findings provide the first molecular basis for the anticarcinogenicaction of anthocyanidins.