Juglone / N-cadherin Cancer Research Results

JG, Juglone: Click to Expand ⟱
Features:
Found in roots, leaves, nut-hulls, bark and wood of walnut trees.
Juglone (5-hydroxy-1,4-naphthoquinone)
Juglans nigra refers to the black walnut tree, which is one of the most well-known sources of juglone
-Research has focused on the hulls (the green outer covering of the walnut) because they have the highest concentrations.
-Fresh hulls can contain juglone levels in the range of approximately 1–5% of the dry weight

-Juglone can redox cycle to generate reactive oxygen species (ROS).
-Increasing Bax, decreasing Bcl‑2, caspase activation, and MMP depolarization.
-Modulation of MAPK pathways (including ERK, JNK, and p38)
-May inhibit NF‑κB signaling
-Cause DNA damage or stress that, in turn, leads to p53 pathway activation— Pin1 Inhibition
–Pin1, a peptidyl-prolyl cis/trans isomerase, is frequently overexpressed in cancer.

-ic50 maybe 5-10uM
-For matching 5uM, crude estimate is 5mg consumption of juglone required which might be 1.5 g of black walnut hull material

Juglone — Juglone (5-hydroxy-1,4-naphthoquinone; JG) is a naturally occurring redox-active naphthoquinone found in plants of the Juglans genus, including black walnut (Juglans nigra), with particularly high concentrations reported in green walnut hulls. It is best classified as a natural small-molecule quinone and experimental anticancer agent rather than an established therapeutic drug. Its anticancer activity is strongly concentration-dependent and reflects electrophilic thiol reactivity, redox cycling, oxidative stress, mitochondrial injury, ferroptosis, apoptosis, and modulation of several oncogenic signaling pathways. Juglone is also widely used experimentally as a Pin1 inhibitor, although this designation should not imply high target selectivity because juglone can covalently modify protein sulfhydryl groups and affect transcription and other cellular proteins.

Primary mechanisms (ranked):

  1. Quinone redox cycling and electrophilic thiol reactivity causing ↑ ROS, ↓ glutathione-dependent antioxidant capacity, oxidative macromolecular injury, and oxidative-stress-driven cell death.
  2. Ferroptosis induction through lipid peroxidation and disruption of antioxidant defenses, including ↓ GPX4 and, in some cancer models, ↓ NRF2 signaling or activation of the FOSL1-HMOX1 axis.
  3. Mitochondrial apoptosis through ↓ mitochondrial membrane potential, ↑ Bax/Bcl-2 ratio, cytochrome-c release, and caspase activation.
  4. Pin1 inhibition contributing to suppression of proliferation, cancer-cell stemness, EMT, migration, angiogenesis, and oncogenic signaling; however, juglone is not a highly selective Pin1 pharmacological probe.
  5. Suppression of PI3K-AKT and related survival signaling, frequently downstream of or amplified by oxidative stress.
  6. Cell-cycle arrest through modulation of cyclins, CDKs, p21, p27, p53, and related checkpoint pathways.
  7. Stress-MAPK modulation, particularly ↑ p38 and ↑ JNK, contributing to apoptosis, ferroptosis, and autophagic responses.
  8. Suppression of EMT, invasion, stem-like phenotype, Wnt/β-catenin signaling, HIF-1α, VEGF, and angiogenic/metastatic programs in selected cancer models.
  9. Autophagy induction as a context-dependent stress response that can interact with apoptosis and oxidative injury.

Bioavailability / PK relevance: Free juglone has unfavorable drug-delivery characteristics, including hydrophobicity, high chemical reactivity, rapid disposition, and substantial renal exposure. In an animal intravenous PK study, free juglone had a plasma half-life of approximately 2 hours and showed prominent kidney localization; sterically stabilized liposomal delivery increased plasma half-life approximately 12-fold, improved tumor localization, and reduced renal toxicity. Robust human oral pharmacokinetic data are lacking. Consequently, dietary or walnut-hull intake cannot presently be converted reliably into a systemic micromolar juglone exposure.

In-vitro vs systemic exposure relevance: Most direct anticancer studies use approximately low-to-tens-of-micromolar juglone, commonly around 5–20 µM. Whether these free-drug concentrations can be maintained safely in human tumors is not established. Recent quantitative work also demonstrates limited intracellular accumulation despite extracellular juglone exposure. Thus, common in-vitro concentrations should not be assumed to be achievable through oral walnut or black-walnut-hull consumption.

Clinical evidence status: Preclinical. Juglone has substantial cell-culture evidence and multiple mouse/xenograft studies showing antitumor activity, including apoptosis, ferroptosis, anti-metastatic, and anti-angiogenic effects. There is no established anticancer dose, regulatory approval, or convincing human clinical efficacy evidence for juglone itself. Translation is limited by nonspecific electrophilic/redox chemistry, systemic toxicity risk, formulation and pharmacokinetic limitations, and the uncertain therapeutic window between cancer and normal tissues.

Juglone Mechanistic Profile

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Quinone redox cycling and thiol reactivity ↑ ROS; ↑ oxidative stress; ↓ cellular thiol buffering ↑ oxidative injury possible P/R Oxidative-stress overload Central upstream mechanism. Juglone participates in redox cycling and can react with protein and glutathione sulfhydryl groups; this contributes to efficacy but also limits selectivity.
2 Glutathione and antioxidant defense ↓ GSH; ↓ GPX4; ↓ SOD (model-dependent) ↓ antioxidant reserve possible (dose-dependent) R Loss of redox buffering Creates a permissive environment for ROS accumulation, lipid oxidation, apoptosis, and ferroptosis.
3 Ferroptosis and lipid peroxidation ↑ ferroptosis; ↑ lipid peroxidation; ↑ MDA; ↑ labile iron Potential ferroptotic toxicity at sufficient exposure R/G Iron-dependent oxidative cell death Strong recent evidence in hepatocellular carcinoma and glioblastoma; pathway execution is cancer-type dependent.
4 NRF2 GPX4 antioxidant axis ↓ NRF2; ↓ GPX4 (model-dependent) Not established R/G Ferroptosis sensitization Demonstrated particularly in glioblastoma. NRF2 modulation should not be generalized to every tumor model.
5 FOSL1 HMOX1 ferroptosis axis ↑ FOSL1; ↑ HMOX1 Not established G Ferroptosis amplification Recent HCC and pan-cancer evidence identifies this transcriptional axis as an important juglone-responsive ferroptotic mechanism.
6 Mitochondrial membrane integrity ↓ membrane potential; ↑ cytochrome-c release Mitochondrial toxicity possible R Intrinsic apoptosis initiation Observed across breast, gastric, prostate, and other cancer models.
7 BAX BCL2 caspase apoptosis ↑ BAX; ↓ BCL2; ↑ caspase-3/7; ↑ caspase-8/9 Apoptosis possible at cytotoxic exposure R/G Programmed cell death Both intrinsic and extrinsic apoptotic pathways can participate. Recent colorectal cancer data support activation of caspase-8 as well as mitochondrial caspase-9 signaling.
8 Pin1 prolyl isomerase ↓ Pin1 activity/function ↓ Pin1 and other thiol-sensitive proteins possible P/R Reduced oncogenic signaling and stemness Important experimental target associated with ↓ proliferation, ↓ EMT, ↓ stemness, and ↓ angiogenesis. Juglone is not Pin1-selective and can directly modify sulfhydryl-containing proteins.
9 PI3K AKT survival signaling ↓ PI3K; ↓ AKT; ↓ p-AKT Context-dependent R/G Survival pathway suppression ROS scavenging can partially reverse this effect in NSCLC, indicating substantial coupling between oxidative stress and PI3K-AKT inhibition.
10 p38 JNK stress signaling ↑ p38; ↑ JNK Context-dependent R Stress-mediated apoptosis and ferroptosis Activation is frequently associated with ROS production and can contribute to NRF2-GPX4 suppression and programmed cell death.
11 Cell cycle checkpoints ↑ arrest; ↓ CDK2; ↓ CDK4; ↓ cyclins; ↑ p21; ↑ p27 Growth inhibition possible G Proliferation blockade Cell-cycle phase varies by model. Recent colorectal cancer data support G0/G1 arrest with suppression of CCND1, CCNB1, CDK2, and CDK4.
12 p53 DNA damage response ↑ DNA damage; ↑ γH2AX; ↑ p53 (model-dependent) Genotoxicity possible R/G Checkpoint activation and apoptosis May arise partly from quinone-driven ROS and electrophilic stress rather than a specific DNA-targeting interaction.
13 Intracellular calcium and mitochondrial stress ↑ Ca²⁺ (model-dependent) Not established P/R Apoptotic signaling Increased intracellular Ca²⁺ has been demonstrated in MCF-7 cells together with ROS elevation and mitochondrial depolarization.
14 EMT migration and invasion ↓ EMT; ↑ E-cadherin; ↓ N-cadherin; ↓ Snail; ↓ migration; ↓ invasion Not established G Reduced metastatic phenotype Pin1, AKT-GSK3β-Snail, TGF-β-related, and other signaling systems have been implicated depending on tumor model.
15 Cancer stemness ↓ sphere formation; ↓ tumor-initiating phenotype Not established G Reduced self-renewal and metastatic potential Pin1 inhibition appears to contribute. Effects have been demonstrated in colorectal and other tumor-initiating cell models.
16 Wnt beta-catenin signaling ↓ Wnt/β-catenin (model-dependent) Not established G Reduced invasion and angiogenesis Most clearly demonstrated in pancreatic cancer models; not necessarily a universal primary mechanism.
17 HIF-1α VEGF angiogenic signaling ↓ HIF-1α; ↓ VEGF; ↓ angiogenesis Potential vascular effects not well characterized G Reduced tumor vascular support Secondary/contextual anticancer mechanism reported in pancreatic cancer and Pin1-related models.
18 Autophagy stress response ↑ LC3-II; ↑ Beclin-1; ↓ p62 (model-dependent) Context-dependent G Autophagic stress and death crosstalk Autophagy can accompany ROS/MAPK signaling but its contribution to net cytotoxicity varies by cell type and experimental conditions.
19 Chemosensitization ↑ drug cytotoxicity in selected combinations Potential ↑ combination toxicity G Combination-treatment sensitization Juglone can enhance etoposide cytotoxicity through Pin1-related mechanisms, but sequence of administration can substantially alter the interaction.
20 Clinical Translation Constraint Effective concentrations commonly ~5–20 µM in vitro Systemic electrophilic and oxidative toxicity limits selectivity G Uncertain therapeutic window Human bioavailability and therapeutic exposure are not established. Free juglone has short animal plasma persistence, renal accumulation, and nephrotoxicity; formulations such as liposomes materially alter PK and distribution.

P: 0–30 min     R: 30 min–3 hr     G: >3 hr

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N-cadherin, N-cadherin: Click to Expand ⟱
Source:
Type:
Also known as Cadherin2 (CDH2).
N-cadherin is a type of cell adhesion molecule that plays a crucial role in the development and maintenance of tissue structure. In the context of cancer, N-cadherin has been implicated in the progression and metastasis of various types of tumors.
N-cadherin expression is increased in various types of cancer.
Normally, N-cadherin is expressed in mesenchymal cells, such as fibroblasts and smooth muscle cells. However, in cancer cells, N-cadherin expression is often upregulated, which can contribute to the epithelial-to-mesenchymal transition (EMT). EMT is a process by which epithelial cells acquire a more mesenchymal phenotype, which is characterized by increased motility, invasiveness, and resistance to apoptosis.
The expression of N-cadherin in cancer cells is closely associated with tumorigenesis and metastasis. Additionally, the soluble N-cadherin level in the serum of cancer patients is much higher than that in the serum of healthy patients, revealing a positive relation with poor prognosis.
Scientific Papers found: Click to Expand⟱
1121- JG,    Juglone suppresses epithelial-mesenchymal transition in prostate cancer cells via the protein kinase B/glycogen synthase kinase-3β/Snail signaling pathway
- in-vitro, Pca, LNCaP
E-cadherin↑, N-cadherin↓, Vim↓, Snail↓, GSK‐3β↑,
5115- JG,    Natural Products to Fight Cancer: A Focus on Juglans regia
- Review, Var, NA
Casp3↑, Casp9↑, MMP↓, AR↓, PSA↓, E-cadherin↑, N-cadherin↓, Vim↓, Akt↓, GSK‐3β↓, EMT↑, TumCI↓, MMP9↓, VEGF↓, MMP2↓, TumCCA↑, ROS↑, Apoptosis↑, GSH↓, Catalase↓, SOD↓, GPx↓, DNAdam↑, γH2AX↑, eff↑, BAX↑, Fas↑, Pin1↓,

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(tgid=1) ⓘ

Catalase↓, 1,   GPx↓, 1,   GSH↓, 1,   ROS↑, 1,   SOD↓, 1,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

MMP↓, 1,  

Cell Death(tgid=5) ⓘ

Akt↓, 1,   Apoptosis↑, 1,   BAX↑, 1,   Casp3↑, 1,   Casp9↑, 1,   Fas↑, 1,  

DNA Damage & Repair(tgid=10) ⓘ

DNAdam↑, 1,   γH2AX↑, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

TumCCA↑, 1,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

EMT↑, 1,   GSK‐3β↓, 1,   GSK‐3β↑, 1,  

Migration(tgid=13) ⓘ

E-cadherin↑, 2,   MMP2↓, 1,   MMP9↓, 1,   N-cadherin↓, 2,   Snail↓, 1,   TumCI↓, 1,   Vim↓, 2,  

Angiogenesis & Vasculature(tgid=14) ⓘ

VEGF↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

PSA↓, 1,  

Hormonal & Nuclear Receptors(tgid=20) ⓘ

AR↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

eff↑, 1,  

Clinical Biomarkers(tgid=22) ⓘ

AR↓, 1,   PSA↓, 1,  

Functional Outcomes(tgid=23) ⓘ

Pin1↓, 1,  
Total Targets: 32

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: N-cadherin, N-cadherin
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#:105  Target#:355  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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