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| Polyphenol found in fruits, vegetables, nuts and some mushrooms. Strawberries, raspberries, blackberries, cherries and walnuts, green tea and red wine. Pomegranate arils are a well known source. Ellagic acid (EA) is a dietary polyphenol found in berries and pomegranate-related foods, with reported anti-inflammatory (NF-κB↓), survival-pathway suppression (PI3K/AKT↓), and anti-proliferative effects including G1 arrest and apoptosis in many cancer models. A key practical nuance is that EA/ellagitannins are extensively transformed by gut microbiota into urolithins, which are more bioavailable and may account for a large share of systemic effects. - Ellagitannins are high molecular weight polyphenols with a complex structure that includes one or more HHDP groups attached to a sugar. - Ellagic Acid is the simpler, bioactive compound released when the HHDP groups in ellagitannins cyclize during hydrolysis. - one best source is raspberries. 100g gives ~50mg(reasonable dose) - Ellagic acid has very poor oral bioavailability - Peak plasma EA after high oral intake is typically: <50–100 nM, often much lower, this is far below concentrations used in many in-vitro anticancer studies (5–50 µM). - efficacy depends on gut metabolism (ie ability to produce Urolithin A) - also look at Urolithin supplements Pathways: Apoptosis Regulation: (Bax, Bad) (Bcl-2, Bcl-xL) Cell Cycle Arrest: G0/G1 or G2/M phases) NF-κB (inhibit): MAPK Pathways: (including ERK1/2, JNK, and p38 MAPK) PI3K/Akt/mTOR: might downregulate this pathway p53 Pathway: may influence the expression or activation of p53 Oxidative Stress and Nrf2 Pathway:exhibits antioxidant properties, Summary: - Anti-oxidant and metal chelating - with some evidence it can induce ROS in cancer tumor conditions (mitochondrial stress, redox-unstable cells) - reported synergy with Curcumin - Reported, reduced the viability of cancer cells at a concentration of 10 µmol/L, while in healthy cells, this effect was observed only at a concentration of 200 µmol/L - Pomegranate juice (PJ) (180 ml) containing EA (25 mg) and ETs (318 mg, as punicalagins, the major fruit ellagitannin). Plasma concentration (31.9 ng/ml) after 1 h post-ingestion but was rapidly eliminated by 4 h. (Hence might be difficult to consume enough EA!!!! to match vitro requirements) - Increased the expression of p53 and p21 proteins as well as markers of apoptosis (Bax and caspase-3), and decreases Bcl-2, NF-кB, and iNOS - EA has restricted bioavailability, primarily due to its hydrophobic nature and very low water solubility. - Processing methods can alter EA content; peel extraction often increases measured EA, while prolonged storage/freezing may reduce levels. Total ellagic acid equivalents (free + bound). Punica granatum L. Pomegranate 700mg/kg (arils), 38700mg/kg(mesocarp) Rubus idaeus L. Raspberry 2637–3309mg/kg jaglandaceae Walnut 410mg/kg(freeEA) 8230mg/kg(totalEA) Ellagic acid — a naturally occurring hydrolysable polyphenol and dilactone derived from hexahydroxydiphenic acid. It occurs as free ellagic acid and, more commonly, as a structural component or hydrolysis product of ellagitannins in pomegranate, raspberries, blackberries, strawberries, walnuts, muscadine grapes, and related foods. It is formally classified as a dietary polyphenolic phytochemical rather than an approved anticancer drug. Oral EA has low aqueous solubility, limited absorption, rapid conjugation, and extensive microbiome-dependent conversion into urolithins; therefore, free EA and its microbial metabolites should be treated as related but pharmacokinetically distinct agents. Primary mechanisms (ranked):
Bioavailability / PK relevance: Free EA has very poor oral bioavailability because of low water solubility, limited intestinal permeability, rapid methylation and glucuronidation, and short systemic persistence. Human plasma exposure to unchanged EA after ellagitannin-rich foods is generally transient and substantially below the micromolar concentrations commonly used in cancer-cell experiments. Gut bacteria convert unabsorbed EA and ellagitannins into urolithins, which circulate mainly as glucuronide or sulfate conjugates and may account for much of the systemic biological activity. Urolithin production varies markedly among individuals according to microbiome metabotype. Liposomal, nanoparticle, phospholipid, and other delivery systems improve exposure experimentally, but none has established clinical anticancer efficacy. In-vitro vs systemic exposure relevance: Many anticancer studies use approximately 5–100 µM EA for hours to days. These concentrations commonly exceed achievable circulating free-EA exposure after food or conventional oral supplementation. Direct relevance is greater for gastrointestinal luminal exposure, local tissue exposure, specialized formulations, or experiments involving metabolites. Results obtained at high micromolar concentrations should not be interpreted as evidence that an ordinary dietary dose will produce equivalent systemic tumor effects. Clinical evidence status: Predominantly preclinical. EA has extensive cell-culture evidence and several animal tumor studies, but human oncology evidence remains limited to an older small adjunctive prostate-cancer trial, observational or combination-product studies, tissue-disposition studies, and trials of ellagitannin-rich pomegranate, berry, or muscadine extracts. These mixed extracts cannot establish EA-specific efficacy. Human randomized trials in metabolic, inflammatory, gastrointestinal, and neurologic conditions provide preliminary safety and biomarker data but do not validate EA as a cancer treatment. EA is not an FDA-approved anticancer agent and should be classified as investigational or dietary adjunct evidence, not established oncology therapy. Safety / interaction constraints: Food-derived exposure is generally well tolerated, and small supplementation trials have not identified a consistent major toxicity signal. Long-term safety of purified high-dose EA in oncology populations is insufficiently characterized. Potential interaction concerns include inhibition or modulation of drug-metabolizing enzymes and transporters, antiplatelet activity, and uncertain effects when combined with cytotoxic chemotherapy or radiotherapy. The antioxidant-versus-pro-oxidant direction is dose-, tissue-, and treatment-dependent; concurrent use during cancer therapy therefore requires clinical review rather than assuming either protection or sensitization. Ellagic Acid Mechanistic Profile
TSF: P: 0–30 min R: 30 min–3 hr G: >3 hr |
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| Tumor cell invasion is a critical process in cancer progression and metastasis, where cancer cells spread from the primary tumor to surrounding tissues and distant organs. This process involves several key steps and mechanisms: 1.Epithelial-Mesenchymal Transition (EMT): Many tumors originate from epithelial cells, which are typically organized in layers. During EMT, these cells lose their epithelial characteristics (such as cell-cell adhesion) and gain mesenchymal traits (such as increased motility). This transition is crucial for invasion. 2.Degradation of Extracellular Matrix (ECM): Tumor cells secrete enzymes, such as matrix metalloproteinases (MMPs), that degrade the ECM, allowing cancer cells to invade surrounding tissues. This degradation facilitates the movement of cancer cells through the tissue. 3.Cell Migration: Once the ECM is degraded, cancer cells can migrate. They often use various mechanisms, including amoeboid movement and mesenchymal migration, to move through the tissue. This migration is influenced by various signaling pathways and the tumor microenvironment. 4.Angiogenesis: As tumors grow, they require a blood supply to provide nutrients and oxygen. Tumor cells can stimulate the formation of new blood vessels (angiogenesis) through the release of growth factors like vascular endothelial growth factor (VEGF). This not only supports tumor growth but also provides a route for cancer cells to enter the bloodstream. 5.Invasion into Blood Vessels (Intravasation): Cancer cells can invade nearby blood vessels, allowing them to enter the circulatory system. This step is crucial for metastasis, as it enables cancer cells to travel to distant sites in the body. 6.Survival in Circulation: Once in the bloodstream, cancer cells must survive the immune response and the shear stress of blood flow. They can form clusters with platelets or other cells to evade detection. 7.Extravasation and Colonization: After traveling through the bloodstream, cancer cells can exit the circulation (extravasation) and invade new tissues. They may then establish secondary tumors (metastases) in distant organs. 8.Tumor Microenvironment: The surrounding microenvironment plays a significant role in tumor invasion. Factors such as immune cells, fibroblasts, and signaling molecules can either promote or inhibit invasion and metastasis. |
| 1621- | EA, | The multifaceted mechanisms of ellagic acid in the treatment of tumors: State-of-the-art |
| - | Review, | Var, | NA |
| 1618- | EA, | A comprehensive review on Ellagic acid in breast cancer treatment: From cellular effects to molecular mechanisms of action |
| - | Review, | BC, | NA |
Query results interpretion may depend on "conditions" listed in the research papers. Such Conditions may include : -low or high Dose -format for product, such as nano of lipid formations -different cell line effects -synergies with other products -if effect was for normal or cancerous cells
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