Dried apple peels were extracted with n-hexane, chloroform, and methanol successively. The portion of the chloroform extract that showed the strongest cytotoxic activity was purified by silica gel chromatography to isolate ursolic acid (UA). The amount of the isolated UA was 0.71% of the dried peels. Normal mouse embryo cells [serum-free mouse embryo (SFME) cells] and tumorigenic human c-Haras-and mouse c-myc-transformed SFME cells [r/m highly metastatic (HM)-SFME-1 cells] were treated with various concentrations of UA (2.5-20 µM) to investigate its effects on cell growth. UA at 10 µM appeared very effective at suppressing the tumor cell growth, affecting more than 82% of r/m HM-SFME-1 cells, while it inhibited cell growth in only about 7% of SFME cells. Tumorigenic r/m HM-SFME-1 cells were also treated with various concentrations (2.5-10 µM) of epidermal growth factor (EGF) or aminoguanidine (AG) in the presence of UA (2.5-10 µM). Neither EGF nor AG seemed to have any effect on UA-inhibited cell growth. In the present study, it is revealed that UA could be a very effective and promising agent for antitumor treatments, * To whom correspondence should be addressed: Department of Pharmacy, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku, Nagoya 468-8503, Japan. Tel.: +81-52-839-2721; Fax: +81-52-834-8090; E-mail: hyamagu@ccmfs. meijo-u.ac.jp as it specifically affects tumorigenic cells yet appears to cause very little harm to normal cells.

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Structural analysis of the high-mobility group protein B1 (HMGB1)-DNA complex and a docking simulation between glycyrrhetinic acid (GA) and the HMGB1-DNA complex were performed with a software package the Molecular Operating Environment (MOE). An HMGB1-DNA (PDB code: 2GZK) was selected for the 3D structure modeling of the HMGB1-DNA complex. The Site Finder module of the MOE identified 16 possible ligand-binding sites in the modeled HMGB1-DNA complex. The docking simulation revealed that GA possibly inhibits functions of HMGB1 interfering with Lys90, Arg91, Ser101, Tyr149, C230 and C231 in the HMGB1-DNA complex. To the best of our knowledge, this is the first report of an HMGB1-DNA complex with GA, and our data verify that the GA-HMGB1-DNA model can be utilized for application to target HMGB1 for the development of antitumor drugs.AbbreviationsASE-Dock - alpha sphere and excluded volume-based ligand-protein docking, CNS - central nervous system, GA - glycyrrhetinic acid, GL - glycyrrhizin, HMGB1 - high-mobility group protein B1, LBS - ligand-biding site, MOE - Molecular Operating Environment, SRY - sex-determining region on the Y chromosome.

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