Skip to main content
SpringerLink
Log in

Ginsenoside compound K inhibits angiogenesis via regulation of sphingosine kinase-1 in human umbilical vein endothelial cells

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Ginsenoside compound K (CK) is a metabolite of the protopanaxadiol-type saponins of Panax ginseng C.A. Meyer (Araliaceae), has long been used to treat against the development of cancer, inflammation, allergies, and diabetes. This study examined the anti-angiogenic properties of CK against sphingosine 1-phosphate (S1P)-induced cell migration via regulation of sphingosine kinase 1 (SPHK1) in human umbilical vein endothelial cells (HUVEC). Studies on S1P-induced cell migration, expression of SPHK1 and MMPs and analysis of sphingolipid metabolites by LC–MS/MS were examined after the treatment of CK (2.5, 5, 10 μg/mL) in HUVEC. S1P produced by SPHK1 is also involved in cell growth, migration, and protection of apoptosis; therefore, we sought to investigate whether ginsenosides are able to regulate SPHK1. For this purpose, we developed an inhibitory assay of SPHK1 activity and an analytical method for detection of S1P and other sphingolipid metabolites in HUVEC. Ginsenoside CK inhibited 100 nM S1P-induced cell migrations in a dose-dependent manner. Among tested ginsenosides, CK exclusively inhibited S1P production, SPHK1 activity and SPHK1 expression in HUVEC, whereas expression of the pro-apoptotic sphingolipids, sphingosine and ceramide, was increased in response to CK. The major subspecies of the increased ceramide was C24:0-ceramide. CK also disrupted the sphingolipid rheostat, which ultimately influences cell fate, and dose-dependently inhibited HUVEC migration by reducing expression of metalloproteinases (MMPs). Ginsenoside CK acts as a unique HUVEC migration inhibitor by regulating MMP expression, as well as the activity of SPHK1 and its related sphingolipid metabolites.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Akao, T., M. Kanaoka, and K. Kobashi. 1998. Appearance of compound K, a major metabolite of ginsenoside Rb1 by intestinal bacteria, in rat plasma after oral administration–measurement of compound K by enzyme immunoassay. Biological and Pharmaceutical Bulletin 21: 245–249.

    Article  CAS  PubMed  Google Scholar 

  • Berdyshev, E.V., I. Gorshkova, P. Usatyuk, S. Kalari, Y. Zhao, N.J. Pyne, S. Pyne, R.A. Sabbadini, J.G. Garcia, and V. Natarajan. 2011. Intracellular S1P generation is essential for S1P-induced motility of human lung endothelial cells: Role of sphingosine kinase 1 and S1P lyase. PLoS ONE 6: e16571.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cheung, L.W., K.W. Leung, C.K. Wong, R.N. Wong, and A.S. Wong. 2011. Ginsenoside-Rg1 induces angiogenesis via non-genomic crosstalk of glucocorticoid receptor and fibroblast growth factor receptor-1. Cardiovascular Research 89: 419–425.

    Article  CAS  PubMed  Google Scholar 

  • Jeong, A., H.J. Lee, S.J. Jeong, E.O. Lee, H. Bae, and S.H. Kim. 2010. Compound K inhibits basic fibroblast growth factor-induced angiogenesis via regulation of p38 mitogen activated protein kinase and AKT in human umbilical vein endothelial cells. Biological and Pharmaceutical Bulletin 33: 945–950.

    Article  CAS  PubMed  Google Scholar 

  • Joh, E.H., I.A. Lee, I.H. Jung, and D.H. Kim. 2011. Ginsenoside Rb1 and its metabolite compound K inhibit IRAK-1 activation–the key step of inflammation. Biochemical Pharmacology 82: 278–286.

    Article  CAS  PubMed  Google Scholar 

  • Kim Do, Y., H.D. Yuan, I.K. Chung, and S.H. Chung. 2009. Compound K, intestinal metabolite of ginsenoside, attenuates hepatic lipid accumulation via AMPK activation in human hepatoma cells. Journal of Agriculture and Food Chemistry 57: 1532–1537.

    Article  Google Scholar 

  • Kluk, M.J., and T. Hla. 2002. Signaling of sphingosine-1-phosphate via the S1P/EDG-family of G-protein-coupled receptors. Biochimica et Biophysica Acta 1582: 72–80.

    Article  CAS  PubMed  Google Scholar 

  • Lee, H.U., E.A. Bae, M.J. Han, N.J. Kim, and D.H. Kim. 2005. Hepatoprotective effect of ginsenoside Rb1 and compound K on tert-butyl hydroperoxide-induced liver injury. Liver Int 25: 1069–1073.

    Article  CAS  PubMed  Google Scholar 

  • Lee, O.H., Y.M. Kim, Y.M. Lee, E.J. Moon, D.J. Lee, J.H. Kim, K.W. Kim, and Y.G. Kwon. 1999. Sphingosine 1-phosphate induces angiogenesis: Its angiogenic action and signaling mechanism in human umbilical vein endothelial cells. Biochemical and Biophysical Research Communications 264: 743–750.

    Article  CAS  PubMed  Google Scholar 

  • Leong, W.I., and J.D. Saba. 2010. S1P metabolism in cancer and other pathological conditions. Biochimie 92: 716–723.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Leung, K.W., H.M. Ng, M.K. Tang, C.C. Wong, R.N. Wong, and A.S. Wong. 2011. Ginsenoside-Rg1 mediates a hypoxia-independent upregulation of hypoxia-inducible factor-1alpha to promote angiogenesis. Angiogenesis 14: 515–522.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Loh, K.C., D. Baldwin, and J.D. Saba. 2011. Sphingolipid signaling and hematopoietic malignancies: To the rheostat and beyond. Anti-Cancer Agents in Medicinal Chemistry 11: 782–793.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Maceyka, M., S.G. Payne, S. Milstien, and S. Spiegel. 2002. Sphingosine kinase, sphingosine-1-phosphate, and apoptosis. Biochimica et Biophysica Acta 1585: 193–201.

    Article  CAS  PubMed  Google Scholar 

  • Ming, Y., Z. Chen, L. Chen, D. Lin, Q. Tong, Z. Zheng, and G. Song. 2011. Ginsenoside compound K attenuates metastatic growth of hepatocellular carcinoma, which is associated with the translocation of nuclear factor-kappaB p65 and reduction of matrix metalloproteinase-2/9. Planta Medica 77: 428–433.

    Article  CAS  PubMed  Google Scholar 

  • Nagahashi, M., S. Ramachandran, E.Y. Kim, J.C. Allegood, O.M. Rashid, A. Yamada, R. Zhao, S. Milstien, H. Zhou, S. Spiegel, and K. Takabe. 2012. Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis. Cancer Research 72: 726–735.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Park, E.K., Y.W. Shin, H.U. Lee, S.S. Kim, Y.C. Lee, B.Y. Lee, and D.H. Kim. 2005. Inhibitory effect of ginsenoside Rb1 and compound K on NO and prostaglandin E2 biosyntheses of RAW264.7 cells induced by lipopolysaccharide. Biological and Pharmaceutical Bulletin 28: 652–656.

    Article  CAS  PubMed  Google Scholar 

  • Sato, K., M. Mochizuki, I. Saiki, Y.C. Yoo, K. Samukawa, and I. Azuma. 1994. Inhibition of tumor angiogenesis and metastasis by a saponin of Panax ginseng, ginsenoside-Rb2. Biological and Pharmaceutical Bulletin 17: 635–639.

    Article  CAS  PubMed  Google Scholar 

  • Shida, D., K. Takabe, D. Kapitonov, S. Milstien, and S. Spiegel. 2008. Targeting SphK1 as a new strategy against cancer. Current Drug Targets 9: 662–673.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Spassieva, S.D., T.D. Mullen, D.M. Townsend, and L.M. Obeid. 2009. Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response. The Biochemical Journal 424: 273–283.

    Article  CAS  PubMed  Google Scholar 

  • Xu, T.M., Y. Xin, M.H. Cui, X. Jiang, and L.P. Gu. 2007. Inhibitory effect of ginsenoside Rg3 combined with cyclophosphamide on growth and angiogenesis of ovarian cancer. Chinese Medical Journal (English) 120: 584–588.

    CAS  Google Scholar 

  • Yan, G., S. Chen, B. You, and J. Sun. 2008. Activation of sphingosine kinase-1 mediates induction of endothelial cell proliferation and angiogenesis by epoxyeicosatrienoic acids. Cardiovascular Research 78: 308–314.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a NRF Grants funded by the Korean Government (MRC, 2010-0029483) and (KRF-2010-0025271).

Author information

Authors and Affiliations

  1. College of Pharmacy and MRC, Chungbuk National University, Cheongju, 361-763, Korea

    Kyong-Oh Shin, Cho-Hee Seo, Hyo-Hyun Cho, Hwan-Soo Yoo, Jin-Tae Hong, Ki-Wan Oh & Yong-Moon Lee

  2. College of Medicine, Ehwa Women’s University, Seoul, 158-710, Korea

    Seikwan Oh

  3. Department of Oriental Pharmaceutical Sciences, Kyung Hee University, Seoul, 130-701, Korea

    Seon-Pyo Hong

Authors
  1. Kyong-Oh Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cho-Hee Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hyo-Hyun Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seikwan Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seon-Pyo Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hwan-Soo Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jin-Tae Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ki-Wan Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yong-Moon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong-Moon Lee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shin, KO., Seo, CH., Cho, HH. et al. Ginsenoside compound K inhibits angiogenesis via regulation of sphingosine kinase-1 in human umbilical vein endothelial cells. Arch. Pharm. Res. 37, 1183–1192 (2014). https://doi.org/10.1007/s12272-014-0340-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-014-0340-6

Keywords

Search

Navigation