Ellagic acid / COX2 Cancer Research Results

EA, Ellagic acid: Click to Expand ⟱
Features:
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

  • P: 0–30 min (primary/rapid effects; early redox interactions)
  • R: 30 min–3 hr (acute stress-response + transcription signaling shifts)
  • G: >3 hr (gene-regulatory adaptation and phenotype-level outcomes)
COX2, cycloocygenase-2 (Cox-2) mRNA and Cox-2 protein: Click to Expand ⟱
Source: HalifaxProj(inhibit)
Type:
Cyclooxygenase-2 (COX-2) is an enzyme that plays a critical role in the conversion of arachidonic acid to prostaglandins, which are lipid compounds involved in various physiological processes, including inflammation, pain, and fever. COX-2 is an inducible enzyme, meaning its expression is typically low in normal tissues but can be upregulated in response to inflammatory stimuli, growth factors, and certain oncogenic signals.
-Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin biosynthesis, plays a key role in inflammation and circulatory homeostasis.
-COX-2 is an inducible enzyme that is upregulated in response to pro-inflammatory signals, including cytokines (e.g., IL-1β, TNF-α) and growth factors.

COX-2 is often overexpressed in various tumors, including colorectal, breast, lung, and prostate cancers.
The prostaglandins produced by COX-2, particularly prostaglandin E2 (PGE2), have several effects that can facilitate cancer progression:
Cell Proliferation: PGE2 can promote the proliferation of cancer cells by activating signaling pathways such as the PI3K/Akt and MAPK pathways.
Nonselective NSAIDs, such as aspirin and ibuprofen, inhibit both COX-1 and COX-2. Epidemiological studies have suggested that regular use of NSAIDs may reduce the risk of certain cancers, particularly colorectal cancer.
Drugs specifically targeting COX-2, such as celecoxib, have been developed.

COX-2 and xanthine oxidase are ROS-producing pro-oxidant enzymes that contribute to inflammation. Elevated COX‑2 levels, often found in inflammatory conditions or certain types of cancers, can contribute to increased production of ROS.
Scientific Papers found: Click to Expand⟱
1620- EA,  Rad,    Radiosensitizing effect of ellagic acid on growth of Hepatocellular carcinoma cells: an in vitro study
- in-vitro, Liver, HepG2
ROS↑, P53↑, TumCCA↑, IL6↓, COX2↓, TNF-α↓, MMP↓, angioG↓, MMP9↓, BAX↑, Casp3↑, Apoptosis↑, RadioS↑, TBARS↑, GSH↓, Bax:Bcl2↑, p‑NF-kB↓, p‑STAT3↓,
1605- EA,    Ellagic Acid and Cancer Hallmarks: Insights from Experimental Evidence
- Review, Var, NA
*BioAv↓, antiOx↓, Inflam↓, TumCP↓, TumCCA↑, cycD1/CCND1↓, cycE/CCNE↓, P53↑, P21↑, COX2↓, NF-kB↓, Akt↑, NOTCH↓, CDK2↓, CDK6↓, JAK↓, STAT3↓, EGFR↓, p‑ERK↓, p‑Akt↓, p‑STAT3↓, TGF-β↓, SMAD3↓, CDK6↓, Wnt/(β-catenin)↓, Myc↓, survivin↓, CDK8↓, PKCδ↓, tumCV↓, RadioS↑, eff↑, MDM2↓, XIAP↓, p‑RB1↓, PTEN↑, p‑FAK↓, Bax:Bcl2↑, Bcl-xL↓, Mcl-1↓, PUMA↑, NOXA↑, MMP↓, Cyt‑c↑, ROS↑, Ca+2↝, Endoglin↑, Diablo↑, AIF↑, iNOS↓, Casp9↑, Casp3↑, cl‑PARP↑, RadioS↑, Hif1a↓, HO-1↓, HO-2↓, SIRT1↓, selectivity↑, Dose∅, NHE1↓, Glycolysis↓, GlucoseCon↓, lactateProd↓, PDK1?, PDK1?, ECAR↝, COX1↓, Snail↓, Twist↓, cMyc↓, Telomerase↓, angioG↓, MMP2↓, MMP9↓, VEGF↓, Dose↝, PD-L1↓, eff↑, SIRT6↑, DNAdam↓,
27- EA,    Ellagic acid inhibits human pancreatic cancer growth in Balb c nude mice
- in-vivo, PC, PANC1
HH↓, Gli1↓, GLI2↓, CDK1/2/5/9↓, p‑Akt↓, NOTCH1↓, Shh↓, Snail↓, E-cadherin↑, NOTCH3↓, HEY1↓, TumCG↓, TumCP↓, Casp3↑, cl‑PARP↑, Bcl-2↓, cycD1/CCND1↓, CDK2↓, CDK6↓, BAX↑, COX2↓, Hif1a↓, VEGF↓, VEGFR2↓, IL6↓, IL8↓, MMP2↓, MMP9↓, NA↓,
1613- EA,    Ellagitannins in Cancer Chemoprevention and Therapy
- Review, Var, NA
ROS↑, angioG↓, ChemoSen↑, BAX↑, Bak↑, Bcl-2↓, Bcl-xL↓, CDK2↓, CDK4↓, CDK6↓, cycD1/CCND1↓, cycE1↓, TumCG↓, VEGF↓, Hif1a↓, eff↑, COX2↓, TumCCA↑, selectivity↑, Wnt/(β-catenin)↓, *toxicity∅,
1607- EA,    Exploring the Potential of Ellagic Acid in Gastrointestinal Cancer Prevention: Recent Advances and Future Directions
- Review, GC, NA
STAT3↓, TumCP↓, Apoptosis↑, NF-kB↓, EMT↓, RadioS↑, antiOx↑, COX1↓, COX2↓, cMyc↓, Snail↓, Twist↓, MMP2↓, P90RSK↓, CDK8↓, PI3K↓, Akt↓, TumCCA↑, Casp8↑, PCNA↓, TGF-β↓, Shh↓, NOTCH↓, IL6↓, ALAT↓, ALP↓, AST↓, VEGF↓, P21↑, *toxicity∅, *Inflam↓, *cardioP↑, *neuroP↑, *hepatoP↑, ROS↑, *NRF2↓, *GSH↑,

Showing Research Papers: 1 to 5 of 5

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 5

Pathway results for Effect on Cancer / Diseased Cells:


NA, unassigned ⓘ

NA↓, 1,  

Redox & Oxidative Stress ⓘ

antiOx↓, 1,   antiOx↑, 1,   GSH↓, 1,   HO-1↓, 1,   HO-2↓, 1,   ROS↑, 4,   TBARS↑, 1,  

Mitochondria & Bioenergetics ⓘ

AIF↑, 1,   MMP↓, 2,   XIAP↓, 1,  

Core Metabolism/Glycolysis ⓘ

ALAT↓, 1,   cMyc↓, 2,   ECAR↝, 1,   GlucoseCon↓, 1,   Glycolysis↓, 1,   lactateProd↓, 1,   PDK1?, 2,   SIRT1↓, 1,  

Cell Death ⓘ

Akt↓, 1,   Akt↑, 1,   p‑Akt↓, 2,   Apoptosis↑, 2,   Bak↑, 1,   BAX↑, 3,   Bax:Bcl2↑, 2,   Bcl-2↓, 2,   Bcl-xL↓, 2,   Casp3↑, 3,   Casp8↑, 1,   Casp9↑, 1,   Cyt‑c↑, 1,   Diablo↑, 1,   HEY1↓, 1,   iNOS↓, 1,   Mcl-1↓, 1,   MDM2↓, 1,   Myc↓, 1,   NOXA↑, 1,   PUMA↑, 1,   survivin↓, 1,   Telomerase↓, 1,  

Transcription & Epigenetics ⓘ

tumCV↓, 1,  

DNA Damage & Repair ⓘ

DNAdam↓, 1,   P53↑, 2,   cl‑PARP↑, 2,   PCNA↓, 1,   SIRT6↑, 1,  

Cell Cycle & Senescence ⓘ

CDK1/2/5/9↓, 1,   CDK2↓, 3,   CDK4↓, 1,   cycD1/CCND1↓, 3,   cycE/CCNE↓, 1,   cycE1↓, 1,   P21↑, 2,   p‑RB1↓, 1,   TumCCA↑, 4,  

Proliferation, Differentiation & Cell State ⓘ

CDK8↓, 2,   EMT↓, 1,   p‑ERK↓, 1,   Gli1↓, 1,   HH↓, 1,   NOTCH↓, 2,   NOTCH1↓, 1,   NOTCH3↓, 1,   P90RSK↓, 1,   PI3K↓, 1,   PTEN↑, 1,   Shh↓, 2,   STAT3↓, 2,   p‑STAT3↓, 2,   TumCG↓, 2,   Wnt/(β-catenin)↓, 2,  

Migration ⓘ

Ca+2↝, 1,   E-cadherin↑, 1,   p‑FAK↓, 1,   GLI2↓, 1,   MMP2↓, 3,   MMP9↓, 3,   PKCδ↓, 1,   SMAD3↓, 1,   Snail↓, 3,   TGF-β↓, 2,   TumCP↓, 3,   Twist↓, 2,  

Angiogenesis & Vasculature ⓘ

angioG↓, 3,   EGFR↓, 1,   Endoglin↑, 1,   Hif1a↓, 3,   VEGF↓, 4,   VEGFR2↓, 1,  

Barriers & Transport ⓘ

NHE1↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX1↓, 2,   COX2↓, 5,   IL6↓, 3,   IL8↓, 1,   Inflam↓, 1,   JAK↓, 1,   NF-kB↓, 2,   p‑NF-kB↓, 1,   PD-L1↓, 1,   TNF-α↓, 1,  

Hormonal & Nuclear Receptors ⓘ

CDK6↓, 4,  

Drug Metabolism & Resistance ⓘ

ChemoSen↑, 1,   Dose↝, 1,   Dose∅, 1,   eff↑, 3,   RadioS↑, 4,   selectivity↑, 2,  

Clinical Biomarkers ⓘ

ALAT↓, 1,   ALP↓, 1,   AST↓, 1,   EGFR↓, 1,   IL6↓, 3,   Myc↓, 1,   PD-L1↓, 1,  
Total Targets: 116

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

GSH↑, 1,   NRF2↓, 1,  

Immune & Inflammatory Signaling ⓘ

Inflam↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 1,  

Functional Outcomes ⓘ

cardioP↑, 1,   hepatoP↑, 1,   neuroP↑, 1,   toxicity∅, 2,  
Total Targets: 8

Scientific Paper Hit Count for: COX2, cycloocygenase-2 (Cox-2) mRNA and Cox-2 protein
5 Ellagic acid
1 Radiotherapy/Radiation
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

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:74  Target#:66  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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