Exploring the Potential of Ellagic Acid in Gastrointestinal Cancer Prevention: Recent Advances and Future Directions

Abstract

Gastrointestinal (GI) cancers are a significant global health concern with diverse etiologies and limited treatment options. Ellagic acid (EA), a natural polyphenolic compound, exhibits promising anticancer properties against various GI malignancies. In this article, we have reviewed recent research on the anticancer potential of EA across esophageal, gastric, colorectal, pancreatic, and liver cancers. In esophageal cancer, EA inhibits the formation of O6-methylguanine (O6-meGua) adducts induced by carcinogens like N-nitrosomethylbenzylamine (NMBA), thereby suppressing tumor growth. Additionally, EA inhibits STAT3 signaling and stabilizes tumor suppressor proteins, showing potential as an anti-esophageal cancer agent. In gastric cancer, EA regulates multiple pathways involved in cell proliferation, invasion, and apoptosis, including the p53 and PI3K-Akt signaling pathways. It also demonstrates anti-inflammatory and antioxidant effects, making it a promising therapeutic candidate against gastric cancer. In colorectal cancer (CRC), EA inhibits cell proliferation, induces apoptosis, and modulates the Wnt/β-catenin and PI3K/Akt pathways, suggesting its efficacy in preventing CRC progression. Furthermore, EA has shown promise in pancreatic cancer by inhibiting nuclear factor-kappa B, inducing apoptosis, and suppressing epithelial-mesenchymal transition. In liver cancer, EA exhibits radio-sensitizing effects, inhibits inflammatory pathways, and modulates the tumor microenvironment, offering potential therapeutic benefits against hepatocellular carcinoma. Studies on EA potential in combination therapies and the development of targeted delivery systems are required for enhanced efficacy against gastrointestinal cancers.

Keywords: Chemopreventive; Ellagic acid; Gastrointestinal malignancies; Gastroprotective; Therapeutic resistance.

Fig. 1

Chemical structure of ellagic acid (C₁₄H₆O₈)

Fig. 2

Figure shows that EA (C14H6O8) induces apoptosis via both intrinsic and extrinsic pathways. It activates death receptors (TNF, TRAILR, FAS), forming the DISC complex and activating caspase 8. Ellagic acid also impacts the PI3K/Akt/mTOR pathway, causing cytochrome c release from mitochondria, which binds Apaf-1 to form the apoptosome, activating caspase 9 and then caspase 3, leading to apoptosis. It modulates Bcl-2 family proteins, inhibits the STAT3/NF-kβ pathway to reduce VEGF expression, and influences transcription factors FOXO3a and RUNX3, collectively promoting apoptotic cell death