Chlorogenic acid, the
ester of
caffeic acid with
quinic acid, is one of the most abundant
polyphenols in the human diet. The
antioxidant and anticarcinogenic properties of
chlorogenic acid have been established in animal studies. However, little is known about the molecular mechanisms through which
chlorogenic acid inhibits
carcinogenesis. In this study, we found that
chlorogenic acid inhibited the proliferation of A549 human
cancer cells in vitro. The results of the soft
agar assay indicated that
chlorogenic acid suppressed 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation of JB6 P+ cells in a dose-dependent manner. Pretreatment of JB6 cells with
chlorogenic acid blocked UVB- or TPA-induced transactivation of
AP-1 and
NF-kappaB over the same dose range. At low concentrations,
chlorogenic acid decreased the phosphorylation of c-Jun NH2-terminal
kinases, p38
kinase, and
MAPK kinase 4 induced by UVB/12-O-tetradecanoylphorbol-13-
acetate, yet higher doses were required to inhibit
extracellular signal-regulated kinases.
Chlorogenic acid also increased the enzymatic activities of
glutathione S-
transferases (GST) and
NAD(P)H:
quinone oxidoreductase. Further studies indicated that
chlorogenic acid could stimulate the nuclear translocation of Nrf2 (NF-E2-related factor) as well as subsequent induction of GSTA1 antioxidant response element (ARE)-mediated GST activity. The
phosphatidylinositol 3-kinase pathway might be involved in the activation of Nrf2 translocation. These results provide the first evidence that
chlorogenic acid could protect against environmental
carcinogen-induced
carcinogenesis and suggest that the chemopreventive effects of
chlorogenic acid may be through its up-regulation of cellular
antioxidant enzymes and suppression of ROS-mediated
NF-kappaB,
AP-1, and MAPK activation.