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Product : EA, Ellagic acid

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)

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 NF-κB inflammatory transcription NF-κB ↓; pro-inflammatory cytokine programs ↓ (context) Inflammation tone ↓ R, G Anti-inflammatory / anti-survival transcription EA is repeatedly reported to suppress NF-κB activity and reduce inflammatory cytokine expression in tumor and inflammation models.
2 PI3K → AKT (± mTOR) survival axis PI3K/AKT ↓ (reported); proliferation ↓ ↔ R, G Growth/survival suppression Multiple cancer studies/reviews report EA-associated suppression of PI3K/AKT signaling linked to G1 arrest and apoptosis.
3 Cell-cycle control (G1 arrest emphasis) Cell-cycle arrest ↑ (often G1); Cyclin/CDK programs ↓ (context) ↔ G Cytostasis Frequently observed as a later phenotype-level outcome; commonly reported alongside reduced proliferation.
4 Intrinsic apoptosis (mitochondrial / caspase-linked) Apoptosis ↑; caspase activation ↑ (context) ↔ (generally less activation) G Apoptosis execution Often downstream of survival signaling suppression and/or stress signaling; reported across multiple tumor types.
5 Nrf2 antioxidant response (Keap1/Nrf2/ARE) Stress adaptation modulation (context-dependent) Nrf2 ↑; antioxidant enzymes ↑ (context) R, G Endogenous antioxidant upshift EA is commonly described as activating Nrf2/ARE programs in oxidative-stress models; tumor direction is model-dependent and should not be overstated.
6 ROS / oxidative stress Oxidative stress tone ↓ (often); ROS direction can vary by model ROS injury ↓ P, R, G Redox buffering (context-dependent) EA is widely characterized as antioxidant/anti-inflammatory; in cancer models, oxidative stress effects can be secondary to pathway reprogramming.
7 Invasion / metastasis programs (MMPs / EMT) MMPs ↓; migration/invasion ↓ (reported) ↔ G Anti-invasive phenotype Often reported as downstream outcomes tied to NF-κB and survival signaling changes; keep as “reported” (not universal).
8 Angiogenesis signaling (VEGF & angiogenic outputs) VEGF ↓; angiogenic outputs ↓ (reported) ↔ G Anti-angiogenic support Typically observed as later reductions in pro-angiogenic expression/secretion or angiogenesis assays.
9 One-carbon / microbiome conversion to urolithins (translation driver) Systemic activity often mediated by urolithins (e.g., urolithin A) rather than free EA — — PK / metabolite constraint EA and ellagitannins are transformed by gut microbiota into urolithins, bioavailable metabolites; inter-individual variation in “metabotypes” affects exposure and effects.
10 Bioavailability constraint (oral exposure) Free EA systemic exposure often limited (without formulation / metabolite reliance) — — Translation constraint EA has absorption/metabolism constraints; measuring metabolites (urolithins) is often more informative than EA alone.

Time-Scale Flag (TSF): P / R / G





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