Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Isolation of epi-Oleanolic Acid from Korean Mistletoe and Its Apoptosis-Inducing Activity in Tumor Cells

  • Jung, Myung-Ju (Division of Applied Biology and Chemistry, College of Agriculture and Life Sciences, Kyungpook National Univer-sity) ;
  • Yoo, Yung-Choon (Department of Microbiology) ;
  • Lee, Kyung-Bok (Department of Biochemistry, School of Medicine, Konyang University) ;
  • Kim, Jong-Bae (Department of Biotechnology and Food Science, Han Dong University) ;
  • Song, Kyung-Sik (Division of Applied Biology and Chemistry, College of Agriculture and Life Sciences, Kyungpook National Univer-sity)
  • Published : 2004.08.01
Download PDF
⟨ Previous Next ⟩

Abstract

A triterpene was isolated as a cytotoxic principle from the dichloromethane extract of Korean mistletoe (KM； Viscum album colora turn) by repeated silica gel chromatography and recrystalli-zation. In in vitro analysis of cytotoxic activity using various human and murine tumor cell lines, the dichloromethane extract of KM was highly cytotoxic against these cells. We isolated the most active compound, referred to VD-3, from the dichloromethane extract of KM. The VD-3 was shown to be less cytotoxic to normal cells (murine splenocytes). From the identification of the chemical structure of VD-3 by spectral data and chemical synthesis, the compound was proven to be epi-oleanolic acid. Tumor cells treated with VD-3 showed a typical pattern of apo-ptotic cell death, such as apparent morphological changes and DNA fragmentation. These results indicate that epi-oleanolic acid is an important compound responsible for antitumor activity of KM.

Keywords

References

  1. Akhtar, N. and Malik, A., Oleanane type triterpenes from Plumeria ruba. Phytochemistry, 32,1523-1525 (1993) https://doi.org/10.1016/0031-9422(93)85171-M
  2. Budzikiewicz, H., Wilson, J. M., and Djerassi, C., Mass spectrometry in structural and stereochemical problems. XX. Pentacyclic triterpenes. J. Am. Chem. Soc., 25, 3688-3699 (1963)
  3. Cainelli, G. and Cardillo, G., Chromium oxidations in organic chemistry. Spring-Velag, Berlin Heidelberg, 173 (1984)
  4. Chem, T. K., Ales, D. C., Baenziger, N. C., and Wiemer, D. F., Anti-repellent triterpenoids from Cordia alliodora. J. Org. Chem. 48, 3525-3231 (1983) https://doi.org/10.1021/jo00168a030
  5. Franz, H., Mistletoe lectins and their A & B chains. Oncology, 43:suppl. 1, 23-28 (1986)
  6. Hajto, T., Hostanska, K., Frei, K., Rordorf, C., and Gabius, H.J., Increased secretion of tumour necrosis factor-${\alpha}$, interleukin 1, and interleukin 6 by human mononuclearcells exposed to ${\beta}$-galactoside lectin from clinically applied mistletoe extract. Cancer Res., 50, 3322-3326 (1990)
  7. Huneck, S., Die Triterpenes uren des Balsams von Liquidambar Orientalis Miller. Tetrahedron, 19, 479-482 (1953) https://doi.org/10.1016/S0040-4020(01)99196-3
  8. Hylands, P. J., Mansour, E. S., and Oskoui, M. T., Bryocoumaric acid, a new triterpene from Bryonia dioica. J. Chem. Soc., Perkin Trans. 1, 2933-2936 (1980)
  9. Jordan, E. and Wagner, H., Structure and properties of polysaccharides from Viscum album (L.), Oncology, 43(Suppl.1), 16-22 (1986) https://doi.org/10.1159/000226416
  10. Khwaja, T. A., Dias, C. B., and Pentecoste, S., Recent studies on the anticancer activities of mistletoe (Viscum album) and its alkaloids. Oncology, 43(Suppl. 1), 42-50 (1986) https://doi.org/10.1159/000226419
  11. Khwaja, T. A., Varven, J. C., Pentecost, S., and Pande, H., Isolation of biologically active alkaloids from Korean mistletoe Viscum album, coloratum. Experimentia, 36, 599-600 (1980) https://doi.org/10.1007/BF01965825
  12. Kuttan, G., Vasudevan, D. M., and Kuttan, R., Effect of a preparation from Viscum album an on tumor development in vitro and in mice. J. Ethnopharmacology, 29, 35-41 (1990) https://doi.org/10.1016/0378-8741(90)90095-B
  13. Kwon, H. C., Lee, K. R., and Zee, O. P., Cytotoxic constituents of Pilea mongolica. Arch. Pharm. Res., 20, 180-183 (1997) https://doi.org/10.1007/BF02974007
  14. Mahato, S. B. and Kundu, A. P.,$^{13}C$-NMR spectra of pentacyclic triterpenoids-A compilation and some salient features. Phytochemistry, 37, 1517-1575 (1994) https://doi.org/10.1016/S0031-9422(00)89569-2
  15. Park, J. H., Hyun C. K., and Shin, H. K., Cytotoxic effects of the compounds in heat-treated mistletoe (Viscum album). Cancer Lett., 139, 207-213 (1999) https://doi.org/10.1016/S0304-3835(99)00043-9
  16. Seo, S., Tomita, Y., and Tori, K., Carbon-13 NMR spectra of urs-12-enes and application to structural assignments of components of Isodon japonicus Hara tissue cultures. Tetrahedron Lett., 7-10 (1975)
  17. Schrader, G. and Apel, K., Isolation and characterization of cDNAs encoding viscotoxins of mistletoe (Viscum album). Eur. J. Biochem., 198, 549-553 (1991) https://doi.org/10.1111/j.1432-1033.1991.tb16049.x
  18. Yagi, A., Okamura, N., Haraguchi, Y., Noda, K., and Nishioka, I., Studies on the constituents of Zizyphi Fructus. II. Structure of new p-coumaroylates of maslinic acid. Chem. Pharm. Bull., 26, 3075-3079 (1978) https://doi.org/10.1248/cpb.26.3075
  19. Yoo, Y. C., Watanabe, R., Koike, Y., Mitobe, M., Shimazaki, K., Watanabe, S., and Azuma, I., Apoptosis in human leukemic cells induced by lactoferricin, a bovine milk-derived peptide: involvement of reactive oxygen species. Biochem. Biophys. Res. Commun., 237, 624-628 (1997) https://doi.org/10.1006/bbrc.1997.7199
  20. Yoon, T. J., Yoo, Y. C., Choi, O. B., Do, M. S., Kang, T. B., Lee, S. W., Azuma, I., and Kim, J. B., Inhibitory effect of Korean mistletoe (Viscum album coloratum) extract on tumor angiogenesis and metastasis of haematogenous and non-haematogenous tumour cells in mice. Cancer Lett., 97, 83-91 (1995) https://doi.org/10.1016/0304-3835(95)03956-W
  21. Yoon, T. J., Yoo, Y. C., Kang, T. B., Baek, Y. J., Huh, C. S., Song, S. K., Lee, K. H., Azuma, I., and Kim, J. B., Prophylactic effect of Korean mistletoe (Viscum album coloratum) extract on tumor metastasis is mediated by enhancement of NK cell activity. Int. J. Immunopharmacol., 20,163-172 (1998) https://doi.org/10.1016/S0192-0561(98)00024-1
  22. Yoon, T. J., Yoo, Y. C., Kang, T. B., Shimazaki, K., Song, S. K., Lee, K. H., Kim, S. H., Park, C. H., Azuma, I., and Azuma, I., Lectins isolated from Korean mistletoe (Viscum album coloratum) induce apoptosis in tumor cells. Cancer Lett., 136, 33-40 (1999) https://doi.org/10.1016/S0304-3835(98)00300-0
  23. Yoon, T. J., Yoo, Y. C., Kang, T. B, Her, E., Kim, S. H., Kim, K., Azuma, I., and Kim, J. B., Cellular and humoral adjuvant activity of lectins isolated from Korean mistletoe (Viscum album coloratum). Int. Immunopharmacol., 1, 881-889 (2001) https://doi.org/10.1016/S1567-5769(01)00024-8
  24. Yoon, T. J., Yoo, Y. C., Kang, T. B., Song, S. K., Lee, K. B., Her, E., Song, K. S., and Kim, J. B., Antitumor activity of the Korean mistletoe lectin is attributed to activation of macrophages and NK cells. Arch. Pharm. Res., 26, 861-867 (2003) https://doi.org/10.1007/BF02980033