Description: <b>Polyphenol</b> 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.<br>
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.<br>
<br>
- Ellagitannins are high molecular weight polyphenols with a complex structure that includes one or more HHDP groups attached to a sugar.<br>
- Ellagic Acid is the simpler, bioactive compound released when the HHDP groups in ellagitannins cyclize during hydrolysis.<br>
- one best source is raspberries. 100g gives ~50mg(reasonable dose)<br>
- Ellagic acid has very poor oral bioavailability<br>
- 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).<br>
- efficacy depends on gut metabolism (ie ability to produce Urolithin A)<br>
- also look at <a href="https://nestronics.ca/dbx/tbProdEdit.php?pid=383">Urolithin</a> supplements<br>
<br>
Pathways:<br>
Apoptosis Regulation: (Bax, Bad) (Bcl-2, Bcl-xL) <br>
Cell Cycle Arrest: G0/G1 or G2/M phases)<br>
NF-κB (inhibit):<br>
MAPK Pathways: (including ERK1/2, JNK, and p38 MAPK) <br>
PI3K/Akt/mTOR: might downregulate this pathway<br>
p53 Pathway: may influence the expression or activation of p53<br>
Oxidative Stress and Nrf2 Pathway:exhibits antioxidant properties, <ROS, may modulate the Nrf2
Angiogenesis Inhibition<br>
<br>
Summary:<br>
- Anti-oxidant and metal chelating<br>
- with some evidence it can induce ROS in cancer tumor conditions (mitochondrial stress, redox-unstable cells) <br>
- reported synergy with Curcumin<br>
- 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<br>
- 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)<br>
- 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<br>
- EA has restricted bioavailability, primarily due to its hydrophobic nature and very low water solubility.<br>
- Processing methods can alter EA content; peel extraction often increases measured EA, while prolonged storage/freezing may reduce levels.<br>
<br>
Total ellagic acid equivalents (free + bound).<br>
Punica granatum L. Pomegranate 700mg/kg (arils), 38700mg/kg(mesocarp)<br>
Rubus idaeus L. Raspberry 2637–3309mg/kg <br>
jaglandaceae Walnut 410mg/kg(freeEA) 8230mg/kg(totalEA)<br>
<br>
<!-- Ellagic Acid (EA) — Time-Scale Flagged Pathway Table (web-page ready) -->
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells</th>
<th>Normal Cells</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>NF-κB inflammatory transcription</td>
<td>NF-κB ↓; pro-inflammatory cytokine programs ↓ (context)</td>
<td>Inflammation tone ↓</td>
<td>R, G</td>
<td>Anti-inflammatory / anti-survival transcription</td>
<td>EA is repeatedly reported to suppress NF-κB activity and reduce inflammatory cytokine expression in tumor and inflammation models.</td>
</tr>
<tr>
<td>2</td>
<td>PI3K → AKT (± mTOR) survival axis</td>
<td>PI3K/AKT ↓ (reported); proliferation ↓</td>
<td>↔</td>
<td>R, G</td>
<td>Growth/survival suppression</td>
<td>Multiple cancer studies/reviews report EA-associated suppression of PI3K/AKT signaling linked to G1 arrest and apoptosis.</td>
</tr>
<tr>
<td>3</td>
<td>Cell-cycle control (G1 arrest emphasis)</td>
<td>Cell-cycle arrest ↑ (often G1); Cyclin/CDK programs ↓ (context)</td>
<td>↔</td>
<td>G</td>
<td>Cytostasis</td>
<td>Frequently observed as a later phenotype-level outcome; commonly reported alongside reduced proliferation.</td>
</tr>
<tr>
<td>4</td>
<td>Intrinsic apoptosis (mitochondrial / caspase-linked)</td>
<td>Apoptosis ↑; caspase activation ↑ (context)</td>
<td>↔ (generally less activation)</td>
<td>G</td>
<td>Apoptosis execution</td>
<td>Often downstream of survival signaling suppression and/or stress signaling; reported across multiple tumor types.</td>
</tr>
<tr>
<td>5</td>
<td>Nrf2 antioxidant response (Keap1/Nrf2/ARE)</td>
<td>Stress adaptation modulation (context-dependent)</td>
<td>Nrf2 ↑; antioxidant enzymes ↑ (context)</td>
<td>R, G</td>
<td>Endogenous antioxidant upshift</td>
<td>EA is commonly described as activating Nrf2/ARE programs in oxidative-stress models; tumor direction is model-dependent and should not be overstated.</td>
</tr>
<tr>
<td>6</td>
<td>ROS / oxidative stress</td>
<td>Oxidative stress tone ↓ (often); ROS direction can vary by model</td>
<td>ROS injury ↓</td>
<td>P, R, G</td>
<td>Redox buffering (context-dependent)</td>
<td>EA is widely characterized as antioxidant/anti-inflammatory; in cancer models, oxidative stress effects can be secondary to pathway reprogramming.</td>
</tr>
<tr>
<td>7</td>
<td>Invasion / metastasis programs (MMPs / EMT)</td>
<td>MMPs ↓; migration/invasion ↓ (reported)</td>
<td>↔</td>
<td>G</td>
<td>Anti-invasive phenotype</td>
<td>Often reported as downstream outcomes tied to NF-κB and survival signaling changes; keep as “reported” (not universal).</td>
</tr>
<tr>
<td>8</td>
<td>Angiogenesis signaling (VEGF & angiogenic outputs)</td>
<td>VEGF ↓; angiogenic outputs ↓ (reported)</td>
<td>↔</td>
<td>G</td>
<td>Anti-angiogenic support</td>
<td>Typically observed as later reductions in pro-angiogenic expression/secretion or angiogenesis assays.</td>
</tr>
<tr>
<td>9</td>
<td>One-carbon / microbiome conversion to urolithins (translation driver)</td>
<td>Systemic activity often mediated by urolithins (e.g., urolithin A) rather than free EA</td>
<td>—</td>
<td>—</td>
<td>PK / metabolite constraint</td>
<td>EA and ellagitannins are transformed by gut microbiota into urolithins, bioavailable metabolites; inter-individual variation in “metabotypes” affects exposure and effects.</td>
</tr>
<tr>
<td>10</td>
<td>Bioavailability constraint (oral exposure)</td>
<td>Free EA systemic exposure often limited (without formulation / metabolite reliance)</td>
<td>—</td>
<td>—</td>
<td>Translation constraint</td>
<td>EA has absorption/metabolism constraints; measuring metabolites (urolithins) is often more informative than EA alone.</td>
</tr>
</table>
<p><b>Time-Scale Flag (TSF):</b> P / R / G</p>
<ul>
<li><b>P</b>: 0–30 min (primary/rapid effects; early redox interactions)</li>
<li><b>R</b>: 30 min–3 hr (acute stress-response + transcription signaling shifts)</li>
<li><b>G</b>: >3 hr (gene-regulatory adaptation and phenotype-level outcomes)</li>
</ul>