Fenofibrate inhibits tumour intravasation by several independent mechanisms in a 3-dimensional co-culture model
| Autor: | Brigitte Kopp, Philipp Saiko, Nicole Huttary, Waranya Chatuphonprasert, Liselotte Krenn, Verena M. Dirsch, Silvio Holzner, Daniela Milovanovic, Junli Hong, Georg Krupitza, Chi Huu Nguyen, Stefan Brenner, Serena Stadler, Walter Jäger, Adryan Fristiohady, Atanas G. Atanasov |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Cell Breast Neoplasms Biology 03 medical and health sciences 0302 clinical medicine Fenofibrate Cytochrome P-450 CYP1A1 medicine Humans skin and connective tissue diseases Oncogene Cell adhesion molecule NF-kappa B Intravasation Endothelial Cells Cancer Cell cycle Intercellular Adhesion Molecule-1 medicine.disease Molecular medicine Coculture Techniques Platelet Endothelial Cell Adhesion Molecule-1 030104 developmental biology medicine.anatomical_structure Oncology Lymphatic Metastasis 030220 oncology & carcinogenesis Cancer cell MCF-7 Cells Cancer research Female Signal Transduction |
| Zdroj: | International Journal of Oncology. 50:1879-1888 |
| ISSN: | 1791-2423 1019-6439 |
| DOI: | 10.3892/ijo.2017.3956 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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