Ellagic Acid Inhibits Bladder Cancer Invasiveness and In Vivo Tumor Growth

• Published in: Nutrients Vol. 8; no. 11; p. 744
• Main Authors: Ceci, Claudia, Tentori, Lucio, Atzori, Maria Grazia, Lacal, Pedro M, Bonanno, Elena, Scimeca, Manuel, Cicconi, Rosella, Mattei, Maurizio, de Martino, Maria Gabriella, Vespasiani, Giuseppe, Miano, Roberto, Graziani, Grazia
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22-11-2016; MDPI
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; B7-H1 Antigen - metabolism; Bladder cancer; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; ellagic acid; Ellagic Acid - pharmacology; Humans; Inhibitory Concentration 50; Male; Mice, Nude; Mitomycin - pharmacology; Neoplasm Invasiveness; Neovascularization, Pathologic; polyphenolic compounds; Signal Transduction - drug effects; Time Factors; Tumor Burden - drug effects; Urinary Bladder Neoplasms - blood supply; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; urothelial cancer; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - drug effects; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGF-A; Xenograft Model Antitumor Assays; urothelial cancer; ellagic acid; VEGF-A; bladder cancer; polyphenolic compounds
• ISSN: 2072-6643; 2072-6643
• DOI: 10.3390/nu8110744

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.