Ellagic acid / TumCI 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)


TumCI, Tumor Cell invasion: Click to Expand ⟱
Source:
Type:
Tumor cell invasion is a critical process in cancer progression and metastasis, where cancer cells spread from the primary tumor to surrounding tissues and distant organs. This process involves several key steps and mechanisms:

1.Epithelial-Mesenchymal Transition (EMT): Many tumors originate from epithelial cells, which are typically organized in layers. During EMT, these cells lose their epithelial characteristics (such as cell-cell adhesion) and gain mesenchymal traits (such as increased motility). This transition is crucial for invasion.

2.Degradation of Extracellular Matrix (ECM): Tumor cells secrete enzymes, such as matrix metalloproteinases (MMPs), that degrade the ECM, allowing cancer cells to invade surrounding tissues. This degradation facilitates the movement of cancer cells through the tissue.

3.Cell Migration: Once the ECM is degraded, cancer cells can migrate. They often use various mechanisms, including amoeboid movement and mesenchymal migration, to move through the tissue. This migration is influenced by various signaling pathways and the tumor microenvironment.

4.Angiogenesis: As tumors grow, they require a blood supply to provide nutrients and oxygen. Tumor cells can stimulate the formation of new blood vessels (angiogenesis) through the release of growth factors like vascular endothelial growth factor (VEGF). This not only supports tumor growth but also provides a route for cancer cells to enter the bloodstream.

5.Invasion into Blood Vessels (Intravasation): Cancer cells can invade nearby blood vessels, allowing them to enter the circulatory system. This step is crucial for metastasis, as it enables cancer cells to travel to distant sites in the body.

6.Survival in Circulation: Once in the bloodstream, cancer cells must survive the immune response and the shear stress of blood flow. They can form clusters with platelets or other cells to evade detection.

7.Extravasation and Colonization: After traveling through the bloodstream, cancer cells can exit the circulation (extravasation) and invade new tissues. They may then establish secondary tumors (metastases) in distant organs.

8.Tumor Microenvironment: The surrounding microenvironment plays a significant role in tumor invasion. Factors such as immune cells, fibroblasts, and signaling molecules can either promote or inhibit invasion and metastasis.


Scientific Papers found: Click to Expand⟱
1618- EA,    A comprehensive review on Ellagic acid in breast cancer treatment: From cellular effects to molecular mechanisms of action
- Review, BC, NA
TumCCA↑, TumCMig↓, TumCI↓, TumMeta↓, Apoptosis↑, TGF-β↓, SMAD3↓, CDK6↓, PI3K↓, Akt↓, angioG↓, VEGFR2↓, MAPK↓, NEDD9↓, NF-kB↓, eff↑, eff↑, RadioS↑, ChemoSen↑, DNAdam↑, eff↑, *toxicity∅, *toxicity∅,
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↑,

Showing Research Papers: 1 to 2 of 2

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 2

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress

GSTs↑, 1,   HO-1↓, 1,   MAD↓, 1,   ROS↑, 1,  

Mitochondria & Bioenergetics

MMP↓, 1,   OCR↓, 1,   XIAP↓, 1,  

Core Metabolism/Glycolysis

AMPK↑, 1,   LDH↓, 1,   PDH↝, 1,   SIRT1↓, 1,  

Cell Death

Akt↓, 2,   Apoptosis↑, 2,   BAX↑, 1,   Bcl-2↓, 1,   Casp3↑, 1,   Cyt‑c↑, 1,   DR4↑, 1,   DR5↑, 1,   MAPK↓, 2,   survivin↓, 1,  

Protein Folding & ER Stress

CHOP↑, 1,   ER Stress↑, 1,  

Autophagy & Lysosomes

LC3II↑, 1,   TumAuto↑, 1,  

DNA Damage & Repair

DNAdam↑, 1,   cl‑PARP↑, 1,   PCNA↓, 1,  

Cell Cycle & Senescence

CDK2↑, 1,   cycD1/CCND1↓, 1,   TumCCA↑, 1,  

Proliferation, Differentiation & Cell State

CIP2A↓, 1,   EMT↓, 1,   NOTCH↓, 2,   PI3K↓, 2,  

Migration

E-cadherin↑, 1,   Ki-67↓, 1,   MMP2↓, 1,   MMP9↓, 1,   NEDD9↓, 1,   PKCδ↓, 1,   SMAD3↓, 1,   Snail↓, 1,   TGF-β↓, 1,   TGF-β↑, 1,   TumCI↓, 2,   TumCMig↓, 1,   TumCP↓, 1,   TumMeta↓, 2,   Vim↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature

angioG↓, 1,   Hif1a↓, 1,   VEGFR2↓, 2,  

Barriers & Transport

GLUT1↓, 1,  

Immune & Inflammatory Signaling

NF-kB↓, 2,   PD-1↓, 1,  

Hormonal & Nuclear Receptors

CDK6↓, 2,  

Drug Metabolism & Resistance

ChemoSen↑, 2,   eff↑, 3,   RadioS↑, 1,  

Clinical Biomarkers

Ki-67↓, 1,   LDH↓, 1,  

Functional Outcomes

AntiCan↑, 1,   ChemoSideEff↓, 1,  
Total Targets: 65

Pathway results for Effect on Normal Cells:


Functional Outcomes

toxicity∅, 2,  
Total Targets: 1

Scientific Paper Hit Count for: TumCI, Tumor Cell invasion
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#:324  State#:%  Dir#:%
wNotes=0 sortOrder:rid,rpid

 

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