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.
Nutrients. 2016 Jan 22*** epublish ***
Claudia Ceci, Lucio Tentori, Maria Grazia Atzori, Pedro M Lacal, Elena Bonanno, Manuel Scimeca, Rosella Cicconi, Maurizio Mattei, Maria Gabriella de Martino, Giuseppe Vespasiani, Roberto Miano, Grazia Graziani
Department of Systems Medicine, University of Rome Tor Vergata, Rome 00173, Italy. ., Department of Systems Medicine, University of Rome Tor Vergata, Rome 00173, Italy. ., Department of Systems Medicine, University of Rome Tor Vergata, Rome 00173, Italy. ., Laboratory of Molecular Oncology, "Istituto Dermopatico dell'Immacolata"-IRCCS, Rome 00167, Italy. ., Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome 00173, Italy. ., Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome 00173, Italy. ., "Centro di Servizi Interdipartimentale, Stazione per la Tecnologia Animale", Department of Biology, University of Rome Tor Vergata, Rome 00173, Italy. ., "Centro di Servizi Interdipartimentale, Stazione per la Tecnologia Animale", Department of Biology, University of Rome Tor Vergata, Rome 00173, Italy. ., Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome 00173, Italy. ., Urology Unit, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome 00173, Italy. ., Urology Unit, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome 00173, Italy. ., Department of Systems Medicine, University of Rome Tor Vergata, Rome 00173, Italy. .