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.

Ellagic Acid Inhibits Extracellular Acidity-Induced Invasiveness and Expression of COX1, COX2, Snail, Twist 1, and c-myc in Gastric Carcinoma Cells

“…This low dose of ellagic acid reduced acidity-promoted expression of MMP7 and MMP9 and inhibited the migrating and matrigel-infiltrating capability of gastric cancer cells, indicating the inhibitory action of ellagic acid against acidity-enhanced invasiveness. Consistently with our study, the inhibitory roles of ellagic acid in multiple metastatic signaling pathways such as wnt/b-catenin, TGF/smad3, HIF1a, and HIF2a have been also demonstrated in several types of cancer cells such as colon, bladder, and breast cancer cells [17,21,34], although the effect of ellagic acid on malignancy caused by acidity has not been elucidated.…”

“…Ellagic acid and ellagic acid-rich foods have shown preventive and therapeutic effects against multiple types of cancers including colorectal cancer, esophageal cancer, breast cancer, prostate cancer, leukemia, and lymphoma [13][14][15]. The anticancer effect of ellagic acid has shown to be mainly mediated through its antiproliferative and pro-apoptotic actions; however, there are also studies indicating that EA inhibits migration and invasion of prostate cancer cells and bladder cancer cells by inhibiting protease activity or reducing the expression of PD-L1 and VEGFR-2 [16,17].Here, we examined the potential of ellagic acid as an anti-invasive agent for gastric cancer cells exposed to an acidic environment. We used AGS and SNU601 GC cell lines maintained under acidic pH culture condition and assessed the effect of ellagic acid on their acidity-promoted invasive activity and the mechanisms involved.…”

Enhanced anticancer activity and oral bioavailability of ellagic acid through encapsulation in biodegradable polymeric nanoparticles

“…[10][11][12] Therapeutically, EA has been proclaimed to be effective in the regression of various kinds of tumors, involving but not limited to lung cancer, colorectal carcinoma, esophageal cancer, metastatic melanoma, hepatocellular carcinoma, tongue cancer, breast cancer, bladder cancer, endometrial carcinoma, and prostate cancer. 4,16,[18][19][20][21][22][23][24][25] Whereas the pharmacological effect of EA has been broadly considered and permitted for the management of a vast spectrum of cancer, it still has poor aqueous solubility and poor bioavailability that offer minimal therapeutic benefit and restrict its full clinical use. 26 Oral administration showed a poor absorption, metabolism in gastrointestinal tract, first-pass effect, and rapid elimination, 19,27,28 which are reported as the main causes of its low bioavailability.…”

Negative Effect of Ellagic Acid on Cytosolic pH Regulation and Glycolytic Flux in Human Endometrial Cancer Cells

“…Development and progression of endometrial cancer is influenced by genetic mutations and epigenetic changes in various cancer-related genes as well as disordered hormone levels [2]. Prophyllaxis and treatment of cancer could be accomplished by Ellagic acid (EA) [3-5], a naturally occurring phenolic constituent of ellagitannins in grapes, nuts, strawberries, blackcurrent, raspberries, green tea, and pomegranate [6]. EA treatment is a new and highly effective strategy in reducing carcinogenesis [7, 8].…”