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ANTI-TUMOR-PROMOTING ACTIVITY OF MAJONOSIDE-R2
A TRITERPENE SAPONIN FROM VIETNAMESE GINSENG


Takao Konoshima,a Midori Takasaki,a Harukuni Tokuda,b Hoyoku Nishino,b
Nguyen Minh Duc,c Ryoji Kasaid and Kazuo Yamasakid


Kyoto Pharmaceutical University,a Kyoto 607-8414, Japan; Kyoto Prefectural University of Medicine,b Kyoto, 602-0000, Japan; Ho Chi Minh City University of Medicine and Pharmacy,c 41 Dinh Tien Hoang, District 1, Ho Chi Minh City, Vietnam; Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine,d Hiroshima 734-8551, Japan

Vietnamese ginseng was discovered in Vietnam in 1973 and named Panax vietnamensis Ha et Grushv. In 1985.[1] This plant was a secret medicine in the Sedang ethnic group living in the higher mountains of the South Annamitic Range (Truong Son Range) in the Western Highland, Central Vietnam. It has been regarded as a miraculous, life-saving plant drug used for the treatment of many serious diseases and for enhancing body strength in long journeys in high mountains.

From the rhizomes and roots of Panax vietnamensis, 37 saponins including 14 new compounds were isolated and characterized.[2-4] Among them, 21 saponins were already isolated from other species of the same genus, such as protopanaxadiol-type saponins: ginsenosides-Rb1 (1, 2.0%), -Rd (2, 0.87%), -Re (3, 0.17%), protopanaxatriol-type saponins: ginsenoside-Rg1 (4, 1.37%), and notoginsenoside R1 (0.36%). In addition, ocotillol-type saponins: majonoside R1 (5, 0.14%) and remarkably high yield of majonoside R2 (6, 5.3%) were identified.

1: R = -Glc6-Glc 3: R = -Glc2-Rha 5: R = -Glc2-Rha

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2: R = -Glc 4: R = -Glc 6: R = -Glc2-Xyl

To search for possible anti-tumor promoters (cancer chemopreventive agents), we screened several plant extracts using the inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA).[5] Methanol extract of Panax vietnamensis showed significant inhibitory activity (37.9 % at 100mg/ml). Since the activity was concentrated to the saponin fraction, the major saponins (1-6) of this plants were tested. Among them, the major saponin, majonoside R2 (6) exhibited the strongest inhibitory effects on EBV-EA activation (50% inhibition at 100 molar ratio/TPA). This activity was much higher than that of glycyrrhetic acid which is known to be a potent anti-tumor-promoter.[6] A series of ocotillol-type saponins from Neoalsomitra integrifoliola[7] was also assayed, and neoalsoside A3 (7) showed the highest activity (36% inhibition at 100 molar ratio/TPA).

The effects of 6 on the cell cycle of Raji cells treated with TPA were examined by flow cytometry. By the treatment with 6, the ratio of S phase of Raji cells was increased, but the ratio of G2 + M phases was decreased in dose-dependent manner. The inhibition mechanism of 6 against cancer promotion of TPA was through influencing the cell cycle.

On the basis of the above in vitro assay, in vivo assay was carried out. The inhibitory effect of 6 on the two-stage carcinogenesis test of mouse skin tumor using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator, and TPA as a promoter. The papilloma production promoted by TPA was significantly decreased and delayed by the pre-treatment of 85 nmol of 6. The activity of 6 was higher than that of glycyrrhetic acid. The inhibitory activity of 6 was also observed when a non-TPA type tumor promoter, fumonsin B1 was used as a promoter.

In conclusion, Vietnamese ginseng promises to be cancer preventive herbal medicine.

References
1. Dung H. T. and Grushvisky I. V., Bot. Jour. Vietnam, 70, 518-522 (1985).
2. Duc N. M., Nham, N. T., Kasai R., Ito, A., Yamasaki, K. and Tanaka, O., Chem. Pharm. Bull., 41, 2010-2014 (1993).
3. Duc N. M., R. Kasai, Ohtani, K., Ito A. Nham, N. T., Yamasaki, K. and Tanaka, O., Chem. Pharm. Bull., 42, 115-122 (1994).
4. Duc N. M., R. Kasai, Ohtani, K., Ito A. Nham, N. T., Yamasaki, K. and Tanaka, O., Chem. Pharm. Bull., 42, 634-640 (1994).
5. Konoshima T, Takasaki M and Tokuda H, Natural Medicines, 50, 158-162 (1996).
6. Tokuda H., Ohigashi H., Koshimizu K. and Ito Y, Cancer Lett., 33, 279-282 (1986).
7. Fujita S., Kasai R., Ohtani K., Yamasaki K, Chiu M-H., Nie R-L. and Tanaka O., Phytochemistry, 38, 465-472 (1995).