Antitumor Effect of Schizandrin by Inhibiting Angiogenesis

Schizandrin의 신혈관형성억제에 의한 항암효과

  • Yoon, Mi So (Department of Cosmetic Science, College of Natural Sciences, Hoseo University) ;
  • Kim, Do Yoon (Department of Cosmetic Science, College of Natural Sciences, Hoseo University) ;
  • Yu, Ho Jin (Department of Cosmetic Science, College of Natural Sciences, Hoseo University) ;
  • Park, Joo-Hoon (Department of Cosmetic Science, College of Natural Sciences, Hoseo University) ;
  • Jang, Sang Hee (Department of Wellbeing Food, Gumi University) ;
  • Won, Kyung-Jong (Department of Physiology, School of Medicine, Konkuk University) ;
  • Kim, Bokyung (Department of Physiology, School of Medicine, Konkuk University) ;
  • Lee, Hwan Myung (Department of Cosmetic Science, College of Natural Sciences, Hoseo University)
  • 윤미소 (호서대학교 한방화장품과학과) ;
  • 김도윤 (호서대학교 한방화장품과학과) ;
  • 유호진 (호서대학교 한방화장품과학과) ;
  • 박주훈 (호서대학교 한방화장품과학과) ;
  • 장상희 (구미대학교 웰빙식품과) ;
  • 원경종 (건국대학교 의과대학 생리학교실) ;
  • 김보경 (건국대학교 의과대학 생리학교실) ;
  • 이환명 (호서대학교 한방화장품과학과)
  • Received : 2012.07.28
  • Accepted : 2012.09.03
  • Published : 2012.10.25

Abstract

Schizandra chinensis extract has been known to possess a variety of efficacy including antitumor. However, it remains unclear how schizandrin, which is a major biological active ingredient of Schizandra chinensis, exerts antitumor effect. This study was designed to investigate the mechanism by which schizandrin inhibits tumor growth and metastasis. In in vivo test using tumor model mice injected with B16BL6 cell line, mice treated with 10 and 100 ${\mu}g/ml$ schizandrin showed a significant inhibition by $73.79{\pm}6.43%$ and $90.46{\pm}1.72%$, respectively, compared with positive tumor controls. Schizandrin did not exert a significant toxicity for the normal cells (HUVECs) and tumor cell lines (A549, B16BL6, Du145, Huh7). Treatment with schizandrin at 10 and 100 ${\mu}g$/head significantly inhibited the tumor-induced angiogenesis by $68.04{\pm}32.21%$ and $103.8{\pm}34.99%$ compared with the positive control group, respectively. Using in vivo lung metastasis model, tumor metastasis assay revealed that 10 and 100 ${\mu}g$/head schizandrin significantly decreased the metastatic lung tumor by $37.51{\pm}8.15%$ and $75.53{\pm}4.38%$ compared with positive controls, respectively. On the other hand, schizandrin did not affect the adherence of B16BL6 cell line to extracellular matrix protein. These results demonstrate that schizandrin exerts inhibitory effect on tumor growth and metastasis by inhibiting angiogenesis. This study thus suggest that schizandrin may be a candidate molecule target for cancer drug development.

Keywords

Acknowledgement

Supported by : 호서대학교

References

  1. Mina, L.A., Sledge, G.W. Jr. Rethinking the metastatic cascade as a therapeutic target. Nat Rev Clin Oncol 8(6):325-332, 2011. https://doi.org/10.1038/nrclinonc.2011.59
  2. Bailer, J.C., Gormick, H.L. Cancer undefeated. N Eng J Med 336: 1567-1575, 1997.
  3. Poprach, A., Petrakova, K., Vyskocil, J., Lakomy, R., Nemecek, R., Kocak, I., Kocakova, I., Vyzula, R. Cardiotoxicity of drugs used in oncology. Klin Onkol 21(5):288-293, 2008.
  4. Lee, S.J., Lee, H.M., Ji, S.T., Lee, S.R., Mar, W., Gho, Y.S. 1,2,3,4,6-Penta-O-galloyl-beta-D-glucose blocks endothelial cell growth and tube formation through inhibition of VEGF binding to VEGF receptor. Cancer Lett 208(1):89-94, 2004. https://doi.org/10.1016/j.canlet.2003.11.008
  5. Han, K.Y., Hong, B.S., Yoon, Y.J., Yoon, C.M., Kim, Y.K., Kwon, Y.G., Gho, Y.S. Polyphosphate blocks tumour metastasis via anti-angiogenic activity. Biochem J 406(1):49-55, 2007. https://doi.org/10.1042/BJ20061542
  6. Folkman, J., Klagsbrun, M. Angiogenic factor. Science 235: 442-447, 1987. https://doi.org/10.1126/science.2432664
  7. Folkman, J., Contran, R. Relation of vascular proliferation to tumor growth. Int Rev Exp Path 16: 207-248, 1976.
  8. Folkman, J. Fundamental concepts of the angiogenic process. Curr Mol Med 3: 643-651, 2003. https://doi.org/10.2174/1566524033479465
  9. Yamakawa, S., Asai, T., Uchida, T., Matsukawa, M., Akizawa, T., Oku, N. (-)-Epigallocatechin gallate inhibits membrane-type 1 matrix metalloproteinase, MT1-MMP, and tumor angiogenesis. Cancer Lett 210: 47-55, 2004. https://doi.org/10.1016/j.canlet.2004.03.008
  10. Igura, K., Ohta, T., Kuroda, Y., Kaji, K. Resveratrol and quercetin inhibit angiogenesis in vitro. Cancer Lett 171: 11-16, 2001. https://doi.org/10.1016/S0304-3835(01)00443-8
  11. Liu, Z., Schwimer, J., Liu, D., Lewis, J., Greenway, F.L., York, D.A., Woltering, E.A. Gallic acid is partially responsible for the antiangiogenic activities of Rubus leaf extract. Phytother Res 20(9):806-813, 2006. https://doi.org/10.1002/ptr.1966
  12. Min, J.K., Han, K.Y., Kim, E.C., et al. Capsaicin inhibits in vitro and in vivo angiogenesis. Cancer Res 64: 644-651, 2004. https://doi.org/10.1158/0008-5472.CAN-03-3250
  13. Yim, S.Y., Lee, Y.J., Lee, Y.K., Jung, S.E., Kim, J.H., Kim, H.J., Son, B.G., Park, Y.H., Lee, Y.G., Choi, Y.W., Hwang, D.Y. Gomisin N isolated from Schisandra chinensis significantly induces anti-proliferative and pro-apoptotic effects in hepatic carcinoma. Mol Med Report 2(5):725-732, 2009.
  14. Park, J.Y., Shin, H.K., Lee, Y.J., Choi, Y.W., Bae, S.S., Kim, C.D. The mechanism of vasorelaxation induced by Schisandra chinensis extract in rat thoracic aorta. J Ethnopharmacol 121(1):69-73, 2009. https://doi.org/10.1016/j.jep.2008.09.031
  15. Li, X.J., Zhao, B.L., Liu, G.T., Xin, W.J. Scavenging effects on active oxygen radicals by schizandrins with different structures and configurations. Free Radic Biol Med 9(2):99-104, 1990. https://doi.org/10.1016/0891-5849(90)90111-U
  16. Kim, S.H., Joo, M.H., Yoo, S.H. Structural identification and antioxidant properties of major anthocyanin extracted from Omija (Schizandra chinensis) fruit. J Food Sci 74(2):C134-140, 2009. https://doi.org/10.1111/j.1750-3841.2009.01049.x
  17. Ikeya, Y., Taguchi, H., Yosioka, I., Kobayashi, H. The constituents of Schizandra chinensis Baill. I. Isolation and structure determination of five new lignans, gomisin A, B, C, F and G, and the absolute structure of schizandrin. Chem Pharm Bull 27(6):1383-1394, 1979. https://doi.org/10.1248/cpb.27.1383
  18. Oh, S.Y., Kim, Y.H., Bae, D.S., Um, B.H., Pan, C.H., Kim, C.Y., Lee, H.J., Lee, J.K. Anti-inflammatory effects of gomisin N, gomisin J, and schisandrin C isolated from the fruit of Schisandra chinensis. Biosci Biotechnol Biochem 74(2):285-291, 2010. https://doi.org/10.1271/bbb.90597
  19. Lu, H., Liu, G.T. Anti-oxidant activity of dibenzocyclooctene lignans isolated from Schisandraceae. Planta Med 58(4):311-313, 1992. https://doi.org/10.1055/s-2006-961473
  20. Jeong, S.I., Kim, S.J., Kwon, T.H., Yu, K.Y., Kim, S.Y. Schizandrin prevents damage of murine mesangial cells via blocking NADPH oxidase-induced ROS signaling in high glucose. Food Chem Toxicol 50(3-4):1045-1053, 2012. https://doi.org/10.1016/j.fct.2011.11.028
  21. Mak, D.H., Ko, K.M. Alterations in susceptibility to carbon tetrachloride toxicity and hepatic antioxidant/detoxification system in streptozotocin-induced short-term diabetic rats: effects of insulin and Schisandrin B treatment. Mol Cell Biochem 175(1-2):225-232, 1997. https://doi.org/10.1023/A:1006883919687
  22. Gu, B.H., Minh, N.V., Lee, S.H., Lim, S.W., Lee, Y.M., Lee, K.S., Kim, D.K. Eoxyschisandrin inhibits H2O2-induced apoptotic cell death in intestinal epithelial cells through nuclear factor-kappaB. Int J Mol Med 26(3):401-406, 2010.
  23. Kronenberg, F., Mindes, J., Jacobson, J.S. The future of complementary and alternative medicine for cancer. Cancer Invest 23: 420-426, 2005. https://doi.org/10.1081/CNV-67159
  24. Dang, C.V., Semenza, G.K., Oncogenic alteration of metabolism. Trends Biochem Sci 24: 68-72, 1999. https://doi.org/10.1016/S0968-0004(98)01344-9