Juglone / Hif1a 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

Rank	Pathway / Target Axis	Direction	Primary Effect	Notes / Cancer Relevance	Ref
1	Redox cycling (quinone–semiquinone system)	↑↑ ROS	Oxidative stress overload	Juglone can act as a redox-cycling quinone; ROS elevation is a dominant upstream driver in multiple cancer models	(ref)
2	Thiol buffering (GSH depletion)	↓ GSH	Loss of redox buffering	In HL-60 leukemia cells, juglone induces ROS and explicitly depletes GSH; antioxidants block downstream apoptosis markers	(ref)
3	Mitochondrial integrity (ΔΨm)	↓ ΔΨm	Mitochondrial dysfunction	In LNCaP prostate cancer cells, juglone decreases mitochondrial potential (ΔΨ) during intrinsic apoptosis	(ref)
4	Intrinsic apoptosis (Caspase-9 → Caspase-3)	↑ Caspase-9/3 activation	Programmed cell death	Same LNCaP evidence base: intrinsic apoptosis with activation of caspases 3 and 9 is reported for juglone	(ref)
5	DNA damage / genotoxic stress	↑ DNA damage	Checkpoint activation and death signaling	Juglone is reported to have genotoxic effects (DNA damage) in melanoma models, consistent with ROS-driven injury	(ref)
6	p53 stress response	↑ p53 pathway (activation)	Cell-cycle arrest / apoptosis cooperation	Human liver cancer model: juglone drives apoptosis and autophagy via a ROS-mediated p53 pathway (in vitro and in vivo)	(ref)
7	MAPK stress pathways (JNK / p38)	↑ JNK / ↑ p38	Pro-death stress signaling	Mechanistic synthesis notes juglone induces ROS and activates JNK and p38 MAPK, contributing to cell death signaling	(ref)
8	NF-κB signaling	↓ NF-κB	Reduced pro-survival transcription	Literature reports juglone inhibits NF-κB production/signaling in colonic cancer cell contexts (noted as prior work)	(ref)
9	PI3K–AKT survival pathway	↓ PI3K / ↓ p-AKT	Survival pathway suppression	NSCLC: juglone increases ROS and inhibits PI3K/Akt signaling; NAC (ROS scavenger) attenuates apoptosis and pathway changes	(ref)
10	Cell cycle control	↑ arrest	Proliferation blockade	NSCLC: juglone arrests the cell cycle alongside ROS rise and apoptosis marker changes	(ref)
11	Autophagy	↑ autophagy (stress-associated)	Stress adaptation / death crosstalk	Juglone induces both apoptosis and autophagy in cancer cells via MAPK pathway modulation (with ROS-MAPK coupling)	(ref)
12	Angiogenesis signaling (VEGF)	↓ VEGF	Reduced vascular support	Pancreatic cancer cell lines: juglone reduces VEGF gene expression (and other metastasis/angiogenesis-related genes) at sub-IC50 exposure	(ref)

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⟱

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

100nM-10uM

Hif1a↓, VEGF↓, p‑Akt↓, TumCP↓, TumCI↓,

Showing Research Papers: 1 to 1 of 1

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:

Cell Death ⓘ

p‑Akt↓, 1,

Migration ⓘ

TumCI↓, 1, TumCP↓, 1,

Angiogenesis & Vasculature ⓘ

Hif1a↓, 1, VEGF↓, 1,
Total Targets: 5

Pathway results for Effect on Normal Cells:

Total Targets: 0

Scientific Paper Hit Count for: Hif1a, HIF1α/HIF1a

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