Archives of Toxicology

, Volume 87, Issue 7, pp 1301–1312 | Cite as

Xanthohumol attenuates tumour cell-mediated breaching of the lymphendothelial barrier and prevents intravasation and metastasis

  • Katharina Viola
  • Sabine Kopf
  • Lucie Rarova
  • Kanokwan Jarukamjorn
  • Nicole Kretschy
  • Mathias Teichmann
  • Caroline Vonach
  • Atanas G. Atanasov
  • Benedikt Giessrigl
  • Nicole Huttary
  • Ingrid Raab
  • Sigurd Krieger
  • Miroslav Strnad
  • Rainer de Martin
  • Philipp Saiko
  • Thomas Szekeres
  • Siegfried Knasmüller
  • Verena M. Dirsch
  • Walter Jäger
  • Michael Grusch
  • Helmut Dolznig
  • Wolfgang Mikulits
  • Georg Krupitza
Biologicals

Abstract

Health beneficial effects of xanthohumol have been reported, and basic research provided evidence for anti-cancer effects. Furthermore, xanthohumol was shown to inhibit the migration of endothelial cells. Therefore, this study investigated the anti-metastatic potential of xanthohumol. MCF-7 breast cancer spheroids which are placed on lymphendothelial cells (LECs) induce “circular chemorepellent-induced defects” (CCIDs) in the LEC monolayer resembling gates for intravasating tumour bulks at an early step of lymph node colonisation. NF-κB reporter-, EROD-, SELE-, 12(S)-HETE- and adhesion assays were performed to investigate the anti-metastatic properties of xanthohumol. Western blot analyses were used to elucidate the mechanisms inhibiting CCID formation. Xanthohumol inhibited the activity of CYP, SELE and NF-kB and consequently, the formation of CCIDs at low micromolar concentrations. More specifically, xanthohumol affected ICAM-1 expression and adherence of MCF-7 cells to LECs, which is a prerequisite for CCID formation. Furthermore, markers of epithelial-to-mesenchymal transition (EMT) and of cell mobility such as paxillin, MCL2 and S100A4 were suppressed by xanthohumol. Xanthohumol attenuated tumour cell-mediated defects at the lymphendothelial barrier and inhibited EMT-like effects thereby providing a mechanistic explanation for the anti-intravasative/anti-metastatic properties of xanthohumol.

Keywords

Xanthohumol Cancer intravasation Lymph endothelium Adhesion Mobility 

Abbreviations

ALOX

Lipoxygenase A

CCIDs

Circular chemorepellent-induced defects

CYP

Cytochrome P450

EMT

Epithelial-to-mesenchymal transition

EROD

Ethoxyresorufin-O-deethylase

HUVEC

Human umbilical vein endothelial cell

ICAM-1

Intercellular adhesion molecule 1

LEC

Lymphendothelial cell

MCL2

Myosin light chain 2

SELE

Selectin E

12(S)-HETE

12(S) Hydroxyeicosatetraenoic acid

Notes

Acknowledgments

We wish to thank Toni Jäger for preparing the figures and to Prof. J. Ulrichova for kind gift of HUVEC cells. Further, Grant Nos. GACR (P505/11/1163) and ED0007/01/01 (both to M.S.) from the Centre of the Region Haná for Biotechnological and Agricultural Research, a grant of the Fellinger foundation (to G.K.), grants of the Herzfelder family foundation (to T.S., H.D., P.S. and M.G.), a grant of the “Hochschuljubilaeumsstiftung der Stadt Wien” grant number H-2498/2011 (to P.S.), a scholarship from the Austrian exchange service OeAD (to K.J.), and grants by the Austrian Science Fund, FWF, grant numbers P19598-B13 and P20905-B13 (to W.M.), S10704-B03 and S10704-B13 (to V.M.D.) and by the European Union, FP7 Health Research, project number HEALTH-F4-2008-202047 (to W.M.) are gratefully acknowledged.

Conflict of interest

None.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Katharina Viola
    • 1
  • Sabine Kopf
    • 1
  • Lucie Rarova
    • 2
  • Kanokwan Jarukamjorn
    • 3
    • 4
  • Nicole Kretschy
    • 1
  • Mathias Teichmann
    • 1
  • Caroline Vonach
    • 1
  • Atanas G. Atanasov
    • 5
  • Benedikt Giessrigl
    • 1
  • Nicole Huttary
    • 1
  • Ingrid Raab
    • 1
  • Sigurd Krieger
    • 1
  • Miroslav Strnad
    • 2
  • Rainer de Martin
    • 6
  • Philipp Saiko
    • 7
  • Thomas Szekeres
    • 7
  • Siegfried Knasmüller
    • 8
  • Verena M. Dirsch
    • 5
  • Walter Jäger
    • 3
  • Michael Grusch
    • 8
  • Helmut Dolznig
    • 9
  • Wolfgang Mikulits
    • 8
  • Georg Krupitza
    • 1
  1. 1.Institute of Clinical PathologyMedical University of ViennaViennaAustria
  2. 2.Centre of the Region Haná for Biotechnological and Agricultural Research, Faculty of SciencePalacký UniversityOlomoucCzech Republic
  3. 3.Department for Clinical Pharmacy and Diagnostics, Faculty of Life SciencesUniversity of ViennaViennaAustria
  4. 4.Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical SciencesKhon Kaen UniversityKhon KaenThailand
  5. 5.Department of PharmacognosyUniversity of ViennaViennaAustria
  6. 6.Department of Vascular Biology and Thrombosis ResearchMedical University of ViennaViennaAustria
  7. 7.Department of Medical and Chemical Laboratory Diagnostics, General Hospital of ViennaMedical University of ViennaViennaAustria
  8. 8.Department of Medicine I, Institute of Cancer ResearchMedical University of ViennaViennaAustria
  9. 9.Institute of Medical GeneticsMedical University of ViennaViennaAustria

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