Ellagic acid / Hif1a 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)
Hif1a, HIF1α/HIF1a: Click to Expand ⟱
Source:
Type:
Hypoxia-Inducible-Factor 1A (HIF1A gene, HIF1α, HIF-1α protein product)
-Dominantly expressed under hypoxia(low oxygen levels) in solid tumor cells
-HIF1A induces the expression of vascular endothelial growth factor (VEGF)
-High HIF-1α expression is associated with Poor prognosis
-Low HIF-1α expression is associated with Better prognosis

-Functionally, HIF-1α is reported to regulate glycolysis, whilst HIF-2α regulates genes associated with lipoprotein metabolism.
-Cancer cells produce HIF in response to hypoxia in order to generate more VEGF that promote angiogenesis

Key mediators of aerobic glycolysis regulated by HIF-1α.
-GLUT-1 → regulation of the flux of glucose into cells.
-HK2 → catalysis of the first step of glucose metabolism.
-PKM2 → regulation of rate-limiting step of glycolysis.
-Phosphorylation of PDH complex by PDK → blockage of OXPHOS and promotion of aerobic glycolysis.
-LDH (LDHA): Rapid ATP production, conversion of pyruvate to lactate;

HIF-1α Inhibitors:
-Curcumin: disruption of signaling pathways that stabilize HIF-1α (ie downregulate).
-Resveratrol: downregulate HIF-1α protein accumulation under hypoxic conditions.
-EGCG: modulation of upstream signaling pathways, leading to decreased HIF-1α activity.
-Emodin: reduce HIF-1α expression. (under hypoxia).
-Apigenin: inhibit HIF-1α accumulation.
Scientific Papers found: Click to Expand⟱
1621- EA,    The multifaceted mechanisms of ellagic acid in the treatment of tumors: State-of-the-art
- Review, Var, NA
AntiCan↑, Apoptosis↑, TumCP↓, TumMeta↓, TumCI↓, TumAuto↑, VEGFR2↓, MAPK↓, PI3K↓, Akt↓, PD-1↓, NOTCH↓, PCNA↓, Ki-67↓, cycD1/CCND1↓, CDK2↑, CDK6↓, Bcl-2↓, cl‑PARP↑, BAX↑, Casp3↑, DR4↑, DR5↑, Snail↓, MMP2↓, MMP9↓, TGF-β↑, PKCδ↓, β-catenin/ZEB1↓, SIRT1↓, HO-1↓, ROS↑, CHOP↑, Cyt‑c↑, MMP↓, OCR↓, AMPK↑, Hif1a↓, NF-kB↓, E-cadherin↑, Vim↓, EMT↓, LC3II↑, CIP2A↓, GLUT1↓, PDH↝, MAD↓, LDH↓, GSTs↑, NOTCH↓, survivin↓, XIAP↓, ER Stress↑, ChemoSideEff↓, ChemoSen↑,
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∅,

Showing Research Papers: 1 to 4 of 4

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 4

Pathway results for Effect on Cancer / Diseased Cells:


NA, unassigned ⓘ

NA↓, 1,  

Redox & Oxidative Stress ⓘ

antiOx↓, 1,   GSTs↑, 1,   HO-1↓, 2,   HO-2↓, 1,   MAD↓, 1,   ROS↑, 3,  

Mitochondria & Bioenergetics ⓘ

AIF↑, 1,   MMP↓, 2,   OCR↓, 1,   XIAP↓, 2,  

Core Metabolism/Glycolysis ⓘ

AMPK↑, 1,   cMyc↓, 1,   ECAR↝, 1,   GlucoseCon↓, 1,   Glycolysis↓, 1,   lactateProd↓, 1,   LDH↓, 1,   PDH↝, 1,   PDK1?, 2,   SIRT1↓, 2,  

Cell Death ⓘ

Akt↓, 1,   Akt↑, 1,   p‑Akt↓, 2,   Apoptosis↑, 1,   Bak↑, 1,   BAX↑, 3,   Bax:Bcl2↑, 1,   Bcl-2↓, 3,   Bcl-xL↓, 2,   Casp3↑, 3,   Casp9↑, 1,   Cyt‑c↑, 2,   Diablo↑, 1,   DR4↑, 1,   DR5↑, 1,   HEY1↓, 1,   iNOS↓, 1,   MAPK↓, 1,   Mcl-1↓, 1,   MDM2↓, 1,   Myc↓, 1,   NOXA↑, 1,   PUMA↑, 1,   survivin↓, 2,   Telomerase↓, 1,  

Transcription & Epigenetics ⓘ

tumCV↓, 1,  

Protein Folding & ER Stress ⓘ

CHOP↑, 1,   ER Stress↑, 1,  

Autophagy & Lysosomes ⓘ

LC3II↑, 1,   TumAuto↑, 1,  

DNA Damage & Repair ⓘ

DNAdam↓, 1,   P53↑, 1,   cl‑PARP↑, 3,   PCNA↓, 1,   SIRT6↑, 1,  

Cell Cycle & Senescence ⓘ

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

Proliferation, Differentiation & Cell State ⓘ

CDK8↓, 1,   CIP2A↓, 1,   EMT↓, 1,   p‑ERK↓, 1,   Gli1↓, 1,   HH↓, 1,   NOTCH↓, 3,   NOTCH1↓, 1,   NOTCH3↓, 1,   PI3K↓, 1,   PTEN↑, 1,   Shh↓, 1,   STAT3↓, 1,   p‑STAT3↓, 1,   TumCG↓, 2,   Wnt/(β-catenin)↓, 2,  

Migration ⓘ

Ca+2↝, 1,   E-cadherin↑, 2,   p‑FAK↓, 1,   GLI2↓, 1,   Ki-67↓, 1,   MMP2↓, 3,   MMP9↓, 3,   PKCδ↓, 2,   SMAD3↓, 1,   Snail↓, 3,   TGF-β↓, 1,   TGF-β↑, 1,   TumCI↓, 1,   TumCP↓, 3,   TumMeta↓, 1,   Twist↓, 1,   Vim↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 2,   EGFR↓, 1,   Endoglin↑, 1,   Hif1a↓, 4,   VEGF↓, 3,   VEGFR2↓, 2,  

Barriers & Transport ⓘ

GLUT1↓, 1,   NHE1↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX1↓, 1,   COX2↓, 3,   IL6↓, 1,   IL8↓, 1,   Inflam↓, 1,   JAK↓, 1,   NF-kB↓, 2,   PD-1↓, 1,   PD-L1↓, 1,  

Hormonal & Nuclear Receptors ⓘ

CDK6↓, 5,  

Drug Metabolism & Resistance ⓘ

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

Clinical Biomarkers ⓘ

EGFR↓, 1,   IL6↓, 1,   Ki-67↓, 1,   LDH↓, 1,   Myc↓, 1,   PD-L1↓, 1,  

Functional Outcomes ⓘ

AntiCan↑, 1,   ChemoSideEff↓, 1,  
Total Targets: 132

Pathway results for Effect on Normal Cells:


Drug Metabolism & Resistance ⓘ

BioAv↓, 1,  

Functional Outcomes ⓘ

toxicity∅, 1,  
Total Targets: 2

Scientific Paper Hit Count for: Hif1a, HIF1α/HIF1a
4 Ellagic acid
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#:143  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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