Juglone / TumCI 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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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⟱
7965- JG,    Mechanistic investigation of Juglone (5-hydroxy-1,4-naphthoquinone) as an anti-cancer agent in human colorectal cancer HCT116 and HT-29 cell lines
- in-vitro, CRC, HCT116 - in-vitro, CRC, HT-29
Apoptosis↑, Casp3↑, Casp7↑, Casp8↑, Casp9↑, Bcl-2↓, TumCCA↑, cycD1/CCND1↓, CycB/CCNB1↓, CDK2↓, CDK4↓, ERK↓, AKT1↓, p38↑, JNK↑, TumCMig↓, TumCI↓, TumMeta↓,
1924- JG,    Juglone triggers apoptosis of non-small cell lung cancer through the reactive oxygen species -mediated PI3K/Akt pathway
- in-vitro, Lung, A549
TumCMig↓, TumCI↓, TumCCA↑, Apoptosis↑, cl‑Casp3↑, BAX↑, Cyt‑c↑, ROS↑, MDA↑, GPx4↓, SOD↓, PI3K↓, Akt↓, eff↓,
974- JG,    Juglone down-regulates the Akt-HIF-1α and VEGF signaling pathways and inhibits angiogenesis in MIA Paca-2 pancreatic cancer in vitro
- in-vitro, PC, MIA PaCa-2
Hif1a↓, VEGF↓, p‑Akt↓, TumCP↓, TumCI↓,
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 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:


Redox & Oxidative Stress(tgid=1) ⓘ

Catalase↓, 1,   GPx↓, 1,   GPx4↓, 1,   GSH↓, 1,   MDA↑, 1,   ROS↑, 2,   SOD↓, 2,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

MMP↓, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

AKT1↓, 1,  

Cell Death(tgid=5) ⓘ

Akt↓, 2,   p‑Akt↓, 1,   Apoptosis↑, 3,   BAX↑, 2,   Bcl-2↓, 1,   Casp3↑, 2,   cl‑Casp3↑, 1,   Casp7↑, 1,   Casp8↑, 1,   Casp9↑, 2,   Cyt‑c↑, 1,   Fas↑, 1,   JNK↑, 1,   p38↑, 1,  

DNA Damage & Repair(tgid=10) ⓘ

DNAdam↑, 1,   γH2AX↑, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

CDK2↓, 1,   CDK4↓, 1,   CycB/CCNB1↓, 1,   cycD1/CCND1↓, 1,   TumCCA↑, 3,  

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

EMT↑, 1,   ERK↓, 1,   GSK‐3β↓, 1,   PI3K↓, 1,  

Migration(tgid=13) ⓘ

E-cadherin↑, 1,   MMP2↓, 1,   MMP9↓, 1,   N-cadherin↓, 1,   TumCI↓, 4,   TumCMig↓, 2,   TumCP↓, 1,   TumMeta↓, 1,   Vim↓, 1,  

Angiogenesis & Vasculature(tgid=14) ⓘ

Hif1a↓, 1,   VEGF↓, 2,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

PSA↓, 1,  

Hormonal & Nuclear Receptors(tgid=20) ⓘ

AR↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

eff↓, 1,   eff↑, 1,  

Clinical Biomarkers(tgid=22) ⓘ

AR↓, 1,   PSA↓, 1,  

Functional Outcomes(tgid=23) ⓘ

Pin1↓, 1,  
Total Targets: 52

Pathway results for Effect on Normal Cells:


Total Targets: 0

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

 

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