Antitumor promotional effects of a novel intestinal bacterial metabolite (IH-901) derived from the protopanaxadiol-type ginsenosides in mouse skin

Abstract

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.