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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 |
| Source: TCGA |
| Type: Antiapoptotic |
| Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress. Thought of as "Master Regulator" of antioxidant response. -One way to estimate Nrf2 induction is through the expression of NQO1. NQO1, the most potent inducer: SFN 0.2 μM, quercetin (2.5 μM), curcumin (2.7 μM), Silymarin (3.6 μM), tamoxifen (5.9 μM), genistein (6.2 μM ), beta-carotene (7.2μM), lutein (17 μM), resveratrol (21 μM), indol-3-carbinol (50 μM), chlorophyll (250 μM), alpha-cryptoxanthin (1.8 mM), and zeaxanthin (2.2 mM) 1. Raising Nrf2 enhances the cell's antioxidant defenses and ↓ROS. This strategy is used to decrease chemo-radio side effects. 2. Downregulating Nrf2 lowers antioxidant defenses and ↑ROS. In cancer cells this leads to DNA damage, and cell death. 3. However there are some cases where increasing Nrf2 paradoxically causes an increase in ROS (cancer cells). Such as cases of Mitochondial overload, signal crosstalk, reductive stress -In some cases, Nrf2 is overexpressed in cancer cells, which can lead to the activation of genes involved in cell proliferation, angiogenesis, and metastasis. This can contribute to the development of resistance to chemotherapy and targeted therapies. -Increased Nrf2 expression: Lung, Breast, Colorectal, Prostrate. Decreased Nrf2 expression: Skine, Liver, Pancreatic. -Nrf2 is a cytoprotective transcription factor which demonstrated both a negative effect as well as a positive effect on cancer - "promotes Nrf2 translocation from the cytoplasm to the nucleus," means facilitates the movement of Nrf2 into the nucleus, thereby enhancing the cell's antioxidant and cytoprotective responses. -Major regulator of Nrf2 activity in cells is the cytosolic inhibitor Keap1. Nrf2 Inhibitors and Activators Nrf2 Inhibitors: Brusatol, Luteolin, Trigonelline, VitC, Retinoic acid, Chrysin Nrf2 Activators: SFN, OPZ EGCG, Resveratrol, DATS, CUR, CDDO, Api - potent Nrf2 inducers from plants include sulforaphane, curcumin, EGCG, resveratrol, caffeic acid phenethyl ester, wasabi, cafestol and kahweol (coffee), cinnamon, ginger, garlic, lycopene, rosemany Nrf2 plays dual roles in that it can protect normal tissues against oxidative damage and can act as an oncogenic protein in tumor tissue. – In healthy tissues, NRF2 activation helps protect cells from oxidative damage and maintains cellular homeostasis. – In many cancers, constitutive activation of NRF2 (often through mutations in NRF2 itself or loss-of-function mutations in KEAP1) leads to an enhanced antioxidant capacity. – This upregulation can promote tumor cell survival by enabling cancer cells to thrive under oxidative stress, resist chemotherapeutic agents, and sustain metabolic reprogramming. – Elevated NRF2 levels have been implicated in promoting tumor growth, metastasis, and resistance to therapy in various malignancies. – High or sustained NRF2 activity is frequently associated with aggressive tumor phenotypes, poorer prognosis, and decreased overall survival in several cancer types. – While its activation is essential for protecting normal cells from oxidative stress, aberrant or sustained NRF2 activation in tumor cells can lead to enhanced survival, therapeutic resistance, and tumor progression. NRF2 inhibitors: (to decrease antioxidant defenses and increase cell death from ROS). -Brusatol: most cited natural inhibitors of Nrf2. -Luteolin: luteolin can reduce Nrf2 activity in specific cancer models and may enhance cell sensitivity to chemotherapy. However, luteolin is also known as an antioxidant, and its influence on Nrf2 can sometimes be context dependent. -Apigenin: certain studies to down‑regulate Nrf2 in cancer cells: Dose and context dependent . -Oridonin: -Wogonin: although its effects might be cell‑ and dose‑specific. - Withaferin A |
| 1607- | EA, | Exploring the Potential of Ellagic Acid in Gastrointestinal Cancer Prevention: Recent Advances and Future Directions |
| - | Review, | GC, | 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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