Epidemiological studies have demonstrated that ginseng intake decreases the risk of
cancer. Ginseng
saponins (
ginsenosides) have been regarded as principal components responsible for the majority of pharmacological activities exerted by ginseng. IH-901 [20-O-beta-d-glucopyranosyl-20(S)-
protopanaxadiol], an intestinal bacterial metabolite derived from
protopanaxadiol-type
saponins of Panax ginseng C.A. Meyer, has been reported to possess antitumor effects, including inhibition of invasion,
metastasis and angiogenesis and induction of
tumor cell apoptosis.
Tumor promotion often accompanies an elevated
ornithine decarboxylase (ODC) activity, acute
inflammation and induction of
cyclooxygenase-2 (COX-2) activity. Here we examined the effects of IH-901 on
tumor promotion and related molecular events in mouse skin in vivo. Mouse ear
edema induced by the prototype
tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) was repressed by IH-901 pre-treatment in a dose-dependent manner. Topical application of IH-901 onto shaven backs of female ICR mice led to the inhibition of TPA-induced expression of COX-2 and production of
prostaglandin E(2). The eukaryotic
transcription factor NF-kappaB has been involved in intracellular signaling pathways associated with
inflammation and
carcinogenesis. IH-901 pre-treatment inhibited TPA-induced epidermal
NF-kappaB DNA binding in mouse skin, which appeared to be mediated by blocking phosphorylation and subsequent degradation of
IkappaBalpha. In an attempt to elucidate the molecular mechanisms by which IH-901 inactivates
NF-kappaB, its effects on activation of upstream signaling
kinases were explored. IH-901 also inhibited the activation of ERK1/2 and Akt signaling. When IH-901 was treated topically prior to TPA, expression and activity of ODC were inhibited dose-dependently. In addition, IH-901 given prior to each topical dose of TPA markedly lowered the number of
papillomas in mouse skin induced by 7,12-dimethylbenz[a]
anthracene. Taken together, these findings suggest that IH-901 exerts anti-inflammatory effects by inhibiting TPA-induced COX-2 expression, which may contribute to its antitumor-promoting effects on mouse skin
carcinogenesis.