title: Fenofibrate inhibits tumour intravasation by several independent mechanisms in a 3-dimensional co-culture model.
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.
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria.
authors.forename: Chi Huu
authors.initials: CH
authors.lastname: Nguyen
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Nicole
authors.initials: N
authors.lastname: Huttary
authors.affiliation: Department of Pharmacognosy, University of Vienna, Vienna, Austria.
authors.forename: Atanas G
authors.initials: AG
authors.lastname: Atanasov
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria.
authors.forename: Waranya
authors.initials: W
authors.lastname: Chatuphonprasert
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Brenner
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria.
authors.forename: Adryan
authors.initials: A
authors.lastname: Fristiohady
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Junli
authors.initials: J
authors.lastname: Hong
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Serena
authors.initials: S
authors.lastname: Stadler
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Silvio
authors.initials: S
authors.lastname: Holzner
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Milovanovic
authors.affiliation: Department of Pharmacognosy, University of Vienna, Vienna, Austria.
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
authors.affiliation: Department of Pharmacognosy, University of Vienna, Vienna, Austria.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Kopp
authors.affiliation: Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria.
authors.forename: Philipp
authors.initials: P
authors.lastname: Saiko
authors.affiliation: Department of Pharmacognosy, University of Vienna, Vienna, Austria.
authors.forename: Liselotte
authors.initials: L
authors.lastname: Krenn
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Jäger
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Krupitza
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018920:Coculture Techniques; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008207:Lymphatic Metastasis; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000235:genetics; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D011345:Fenofibrate