title: Ellagic Acid Inhibits Bladder Cancer Invasiveness and In Vivo Tumor Growth.
abstract: Ellagic acid (EA) is a polyphenolic compound that can be found as a naturally occurring hydrolysis product of ellagitannins in pomegranates, berries, grapes, green tea and nuts. Previous studies have reported the antitumor properties of EA mainly using in vitro models. No data are available about EA influence on bladder cancer cell invasion of the extracellular matrix triggered by vascular endothelial growth factor-A (VEGF-A), an angiogenic factor associated with disease progression and recurrence, and tumor growth in vivo. In this study, we have investigated EA activity against four different human bladder cancer cell lines (i.e., T24, UM-UC-3, 5637 and HT-1376) by in vitro proliferation tests (measuring metabolic and foci forming activity), invasion and chemotactic assays in response to VEGF-A and in vivo preclinical models in nude mice. Results indicate that EA exerts anti-proliferative effects as a single agent and enhances the antitumor activity of mitomycin C, which is commonly used for the treatment of bladder cancer. EA also inhibits tumor invasion and chemotaxis, specifically induced by VEGF-A, and reduces VEGFR-2 expression. Moreover, EA down-regulates the expression of programmed cell death ligand 1 (PD-L1), an immune checkpoint involved in immune escape. EA in vitro activity was confirmed by the results of in vivo studies showing a significant reduction of the growth rate, infiltrative behavior and tumor-associated angiogenesis of human bladder cancer xenografts. In conclusion, these results suggest that EA may have a potential role as an adjunct therapy for bladder cancer.
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome 00173, Italy. claudiaceci@hotmail.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ceci
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome 00173, Italy. tentori@uniroma2.it.
authors.forename: Lucio
authors.initials: L
authors.lastname: Tentori
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome 00173, Italy. mariagraziaatzori.2@gmail.com.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Atzori
authors.affiliation: Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Rome 00167, Italy. p.lacal@idi.it.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Lacal
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome 00173, Italy. elena.bonanno@uniroma2.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Bonanno
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome 00173, Italy. manuel.scimeca@uniroma2.it.
authors.forename: Manuel
authors.initials: M
authors.lastname: Scimeca
authors.affiliation: "Centro di Servizi Interdipartimentale, Stazione per la Tecnologia Animale", Department of Biology, University of Rome Tor Vergata, Rome 00173, Italy. rosella.cicconi@uniroma2.it.
authors.forename: Rosella
authors.initials: R
authors.lastname: Cicconi
authors.affiliation: "Centro di Servizi Interdipartimentale, Stazione per la Tecnologia Animale", Department of Biology, University of Rome Tor Vergata, Rome 00173, Italy. mattei@uniroma2.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Mattei
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome 00173, Italy. maria.gabriella.de.martino@uniroma2.it.
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: de Martino
authors.affiliation: Urology Unit, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome 00173, Italy. vespasiani@med.uniroma2.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Vespasiani
authors.affiliation: Urology Unit, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome 00173, Italy. mianor@virgilio.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Miano
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome 00173, Italy. graziani@uniroma2.it.
authors.forename: Grazia
authors.initials: G
authors.lastname: Graziani
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D060890:B7-H1 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004610:Ellagic Acid / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008819:Mice, Nude; D016685:Mitomycin / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004610:Ellagic Acid; D016685:Mitomycin; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: VEGF-A; bladder cancer; ellagic acid; polyphenolic compounds; urothelial cancer