Anti-tumor-Promoting Activities of Agaro-Oligosaccharides on Two-Stage Mouse Skin Carcinogenesis

Abstract

We have previously reported that agaro-oligosaccharides (AGOs) suppressed the elevated levels of nitric oxide (NO), prostaglandin E 2 (PGE 2 ), and pro-inflammatory cytokines in activated monocytes/macrophages, via heme oxygenase-1 induction. In this report, we initially demonstrated that AGOs intake inhibited NO production in activated peritoneal macrophages. Then, we tested for the ability of AGOs to prevent tumor promotion on the two-stage mouse skin carcinogenesis model. As a result, AGOs feeding led to delayed tumor appearance and decreased tumor number. It is known that PGE 2 is one of key players in carcinogenesis. Thus, we confirmed that PGE 2 production was suppressed by AGOs intake in TPA-induced ear edema model. We also demonstrated that cyclooxygenase-2 and microsomal PGE synthase-1, rate-limiting enzymes in PGE 2 production, were down-regulated by AGOs in human monocytes. Consequently, AGOs are expected to prevent tumor promotion by inhibiting PGE 2 elevation in chronic inflammation site.Key words agaro-oligosaccharide; anti-inflammation; cancer chemoprevention Agarose, the main component of polysaccharide in agar, is composed of the alternating residues of 3-O-linked β-Dgalactopyranose (Gal) and 4-O-linked 3,6-anhydro-α-Lgalactopyranose (Ah-Gal).1) When agarose is treated by mild acidic conditions, the α1 3 linkage is hydrolyzed, and then yielding agaro-oligosaccharides (AGOs) that have repeating agarobiose (AB) units, with Gal at the non-reducing end and Ah-Gal at the reducing end (Fig. 1). We previously reported that AGOs suppress the elevated levels of nitric oxide (NO), prostaglandin E 2 (PGE 2 ), and pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β and interleukin-6 in lipopolysaccharide (LPS)-stimulated monocytes and macrophages.2) These pro-inflammatory mediators have been implicated in the pathogenesis of inflammatory diseases such as rheumatoid arthritis (RA) and carcinogenesis.3-5) Elevated levels of NO and PGE 2 have been observed in the synovial fluid of RA patients, and excessive NO or PGE 2 contribute to inflammation-related carcinogenesis. [6][7][8][9][10] The activated macrophages at the sites of inflammation persistently express inducible NO synthase (iNOS), resulting in the production of a large amount of NO which interacts with other free radicals (superoxide anions) to form the highly toxic peroxynitrite. 11)Also, overproduced PGE 2 increases the blood flow and potentiates edema and hyperalgesia. 12) It has been shown that AGOs can suppress the excess NO and PGE 2 production via heme oxygenase-1 induction.2) Further, with respect to NO suppression, we confirmed that iNOS expression is inhibited by AGOs treatment, and showed the inhibition of pro-inflammatory mediators release in activated macrophages in vitro. Thus, AGOs were expected to elicit their beneficial effects on subjects having chronic inflammation state such as carcinogenesis.The aim of this study is to demonstrate whether AGOs exert the anti-tumor-promoting activity on well-established mouse...

Anti-Obesity and Anti-Diabetic Effect of Neoagarooligosaccharides on High-Fat Diet-Induced Obesity in Mice

“…In recent years, bioactivity studies have demonstrated that (N)AOs exhibit a variety of physiological activities. For instances, AOs were reported to have antitumor activity against mouse skin carcinogenesis [8], antioxidant activity, and hepatoprotective potential [9]. NAOs were reported to inhibit the growth of bacteria, slow down the degradation of starch, and be used as low-calorie additives to improve food quality [2].…”

Isolation and Characterization of an Agaro-Oligosaccharide (AO)-Hydrolyzing Bacterium from the Gut Microflora of Chinese Individuals

“…Ramnani et al reported that agaro-oligosaccharides with molecular weights of 64.64 KDa could induce significant increases in the population of bifidobacteria in an in vitro fermentation system inoculated with the human intestinal microbiota [9]. In addition, agaro-oligosaccharides have shown a range of health-promoting activities, such as anti-tumor [10], anti-inflammatory [11]–[13] and anti-oxidant properties [14]. The specific beneficial effects of AO are usually associated with specific degrees of polymerization (DP).…”

Therapeutic Spectrum of Nondigestible Oligosaccharides: Overview of Current State and Prospect

“…Gao and others () investigated the in vitro effect and mechanism of inhibition and apoptosis of human ovarian cancer SKOV‐3 cells by COS and reported efficient inhibition of cell proliferation and apoptosis induction in a dose‐dependent manner. Enoki and others () observed that AOS feeding led to delayed appearance and decreased number of tumors in 2‐stage mouse skin carcinogenesis model. The production of PGE 2 (a key player in carcinogenesis) was suppressed by AOS intake in 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) induced ear edema model.…”