title: Tesmilifene modifies brain endothelial functions and opens the blood-brain/blood-glioma barrier.
abstract: Tesmilifene, a tamoxifen analog with antihistamine action, has chemopotentiating properties in experimental and clinical cancer studies. In our previous works, tesmilifene increased the permeability of the blood-brain barrier (BBB) in animal and culture models. Our aim was to investigate the effects of tesmilifene on brain microvessel permeability in the rat RG2 glioma model and to reveal its mode of action in brain endothelial cells. Tesmilifene significantly increased fluorescein extravasation in the glioma. Short-term treatment with tesmilifene reduced the resistance and increased the permeability for marker molecules in a rat triple co-culture BBB model. Tesmilifene also affected the barrier integrity in brain endothelial cells co-cultured with RG2 glioblastoma cells. Tesmilifene inhibited the activity of P-glycoprotein and multidrug resistance-associated protein-1 efflux pumps and down-regulated the mRNA expression of tight junction proteins, efflux pumps, solute carriers, and metabolic enzymes important for BBB functions. Among the possible signaling pathways that regulate BBB permeability, tesmilifene activated the early nuclear translocation of NFκB. The MAPK/ERK and PI3K/Akt kinase pathways were also involved. We demonstrate for the first time that tesmilifene increases permeability marker molecule extravasation in glioma and inhibits efflux pump activity in brain endothelial cells, which may have therapeutic relevance. Tesmilifene, a chemopotentiator in experimental and clinical cancer studies increases vascular permeability in RG2 glioma in rats and permeability for marker molecules in a culture model of the blood-brain barrier. Tesmilifene inhibits the activity of efflux pumps and down-regulates the mRNA expression of tight junction proteins, transporters, and metabolic enzymes important for the blood-brain barrier functions, which may have therapeutic relevance.
authors.affiliation: Group of Biological Barriers, Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Fruzsina R
authors.initials: FR
authors.lastname: Walter
authors.affiliation: Group of Biological Barriers, Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Szilvia
authors.initials: S
authors.lastname: Veszelka
authors.affiliation: Group of Biological Barriers, Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.|Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Mária
authors.initials: M
authors.lastname: Pásztói
authors.affiliation: Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary.
authors.forename: Zoltán A
authors.initials: ZA
authors.lastname: Péterfi
authors.affiliation: Faculty of Science and Informatics, Department of Biotechnology, University of Szeged, Szeged, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Tóth
authors.affiliation: Faculty of Science and Informatics, Department of Biotechnology, University of Szeged, Szeged, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Rákhely
authors.affiliation: Research Laboratory, 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Cervenak
authors.affiliation: Group of Biological Barriers, Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Csongor S
authors.initials: CS
authors.lastname: Ábrahám
authors.affiliation: Group of Biological Barriers, Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Mária A
authors.initials: MA
authors.lastname: Deli
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001932:Brain Neoplasms / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D005910:Glioma / Q000473:pathology; D006633:Histamine Antagonists / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D010647:Phenyl Ethers / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D006633:Histamine Antagonists; D010647:Phenyl Ethers; C043062:tesmilifene
keywords: blood-brain barrier; brain endothelial cells; glioma; permeability; tesmilifene; tight junctions