Fenofibrate inhibits tumour intravasation by several independent mechanisms in a 3-dimensional co-culture model

  • Authors:
    • Chi Huu Nguyen
    • Nicole Huttary
    • Atanas G. Atanasov
    • Waranya Chatuphonprasert
    • Stefan Brenner
    • Adryan Fristiohady
    • Junli Hong
    • Serena Stadler
    • Silvio Holzner
    • Daniela Milovanovic
    • Verena M. Dirsch
    • Brigitte Kopp
    • Philipp Saiko
    • Liselotte Krenn
    • Walter Jäger
    • Georg Krupitza
  • View Affiliations

  • Published online on: April 7, 2017     https://doi.org/10.3892/ijo.2017.3956
  • Pages:1879-1888
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Abstract

Lymph node metastasis of breast cancer is a clinical marker of poor prognosis. Yet, there exist no therapies targeting mechanisms of intravasation into lymphatics. Herein we report on an effect of the antidyslipidemic drug fenofibrate with vasoprotective activity, which attenuates breast cancer intravasation in vitro, and describe the potential mechanisms. To measure intravasation in a 3-dimensional co-culture model MDA-MB231 and MCF-7 breast cancer spheroids were placed on immortalised lymphendothelial cell (LEC) monolayers. This provokes the formation of circular chemorepellent induced defects (CCIDs) in the LEC barrier resembling entry ports for the intravasating tumour. Furthermore, the expression of adhesion molecules ICAM-1, CD31 and FAK was investigated in LECs by western blotting as well as cell-cell adhesion and NF-κB activity by respective assays. In MDA-MB231 cells the activity of CYP1A1 was measured by EROD assay. Fenofibrate inhibited CCID formation in the MDA-MB231/LEC- and MCF-7/LEC models and the activity of NF-κB, which in turn downregulated ICAM-1 in LECs and the adhesion of cancer cells to LECs. Furthermore, CD31 and the activity of FAK were inhibited. In MDA-MB231 cells, fenofibrate attenuated CYP1A1 activity. Combinations with other FDA-approved drugs, which reportedly inhibit different ion channels, attenuated CCID formation additively or synergistically. In summary, fenofibrate inhibited NF-κB and ICAM-1, and inactivated FAK, thereby attenuating tumour intravasation in vitro. A combination with other FDA-approved drugs further improved this effect. Our new concept may lead to a novel therapy for cancer patients.

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May 2017
Volume 50 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

2016 Impact Factor: 3.079
Ranked #33/217 Oncology
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APA
Nguyen, C.H., Huttary, N., Atanasov, A.G., Chatuphonprasert, W., Brenner, S., Fristiohady, A. ... Krupitza, G. (2017). Fenofibrate inhibits tumour intravasation by several independent mechanisms in a 3-dimensional co-culture model. International Journal of Oncology, 50, 1879-1888. https://doi.org/10.3892/ijo.2017.3956
MLA
Nguyen, C. H., Huttary, N., Atanasov, A. G., Chatuphonprasert, W., Brenner, S., Fristiohady, A., Hong, J., Stadler, S., Holzner, S., Milovanovic, D., Dirsch, V. M., Kopp, B., Saiko, P., Krenn, L., Jäger, W., Krupitza, G."Fenofibrate inhibits tumour intravasation by several independent mechanisms in a 3-dimensional co-culture model". International Journal of Oncology 50.5 (2017): 1879-1888.
Chicago
Nguyen, C. H., Huttary, N., Atanasov, A. G., Chatuphonprasert, W., Brenner, S., Fristiohady, A., Hong, J., Stadler, S., Holzner, S., Milovanovic, D., Dirsch, V. M., Kopp, B., Saiko, P., Krenn, L., Jäger, W., Krupitza, G."Fenofibrate inhibits tumour intravasation by several independent mechanisms in a 3-dimensional co-culture model". International Journal of Oncology 50, no. 5 (2017): 1879-1888. https://doi.org/10.3892/ijo.2017.3956