Propolis -bee glue / NRF2 Cancer Research Results

PBG, Propolis -bee glue: Click to Expand ⟱

Features: Compound

Brazilian Green Propolis often considered best
• Derived from Baccharis dracunulifolia, this type is rich in artepillin C.
• It has been widely researched for its anticancer, anti-inflammatory, and antioxidant properties.
-Propolis common researched flavonoids :chrysin, pinocembrin, galangin, pinobanksin(Pinocembrin)
-most representative phenolic acids were caffeic acid, p-coumaric acid, and ferulic acid, as well as their derivatives, DMCA and caffeic acid prenyl, benzyl, phenylethyl (CAPE), and cinnamyl esters
-One of the most studied active compounds of a poplar-type propolis is caffeic acid phenethyl ester (CAPE)
-caffeic acid phenethyl ester (CAPE), galangin, chrysin, nemorosone, propolin G, artepillin C, cardanol, pinocembrin, pinobanksin, chicoric acid, and phenolic acids (caffeic acid, ferulic acid, and coumaric acid), as well as luteolin, apigenin, myricetin, naringenin, kaempferol, quercetin, polysaccharides, tannins, terpenes, sterols, and aldehydes -content highly variable based on location and extraction
Two main factors of interest:
1. affects interstitual fluild pH
2. high concentration raises ROS (Reactive Oxygen Species), while low concentration may reduce ROS

- Artepillin-C (major phenolic compounds found in Brazilian green propolis (BGP))
- caffeic acid major source

Propolis is chemically diverse (300+ compounds reported) and composition depends on botanical/geographic source.
Antibacterial activity is documented in classic literature (often stronger against Gram+).
CAPE from propolis has reported preferential tumor cytotoxicity in early landmark work (often cited in antimicrobial paper references)

Do not combine with 2DG

Pathways:
-Propolis compounds (e.g., artepillin C, caffeic acid phenethyl ester [CAPE]) can trigger apoptosis (programmed cell death) in cancer cells.
-Propolis has been shown to inhibit NF‑κB activation.
-Propolis extracts can cause cell cycle arrest at specific checkpoints (e.g., G0/G1 or G2/M phases).
-Enhance the body’s antitumor immune responses, for example by activating natural killer (NK) cells and modulating cytokine profiles.

-Note half-life no standard, high variablity of content.
BioAv poor water solubility, and low oral bioavailability.
Pathways:
- high concentration may induce ROS production, while low concentrations mya low it. This may apply to both normal and cancer cells. Normal Cells Example. (Also not sure if high level are acheivable in vivo due to bioavailability)
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓, Prx,
SOD↓, GSH↓ Catalase↓ HO1↓ GPx↓ -->
- Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑">NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, Pro-Inflammatory Cytokines : NLRP3↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, IGF-1↓, uPA↓, VEGF↓, ROCK1↓, FAK↓, RhoA↓, NF-κB↓, TGF-β↓, α-SMA↓, ERK↓
- reactivate genes thereby inhibiting cancer cell growth : HDAC↓, P53↑,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, TNF-α↓, FAK↓, ERK↓, EMT↓, TOP1↓, TET1,
- inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, GRP78↑, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓,
- Others: PI3K↓, AKT↓, STAT↓, β-catenin↓, AMPK, ERK↓, JNK,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,

- Selectivity: Cancer Cells vs Normal Cells

Rank	Pathway / Axis	Cancer Cells	Normal Cells	TSF	Primary Effect	Notes / Interpretation
1	ROS / redox stress (context-selective)	Often ↑ ROS / oxidative stress susceptibility (P→R→G)	Often antioxidant / cytoprotective in inflammatory stress contexts (R→G)	P, R, G	Stress amplifier / selectivity gate	Net ROS direction is highly context- and extract-dependent; propolis chemistry varies by geography/plant source and can shift redox behavior.
2	NF-κB inflammatory transcription	↓ NF-κB activity (R→G)	Anti-inflammatory signaling in immune/tissue contexts (R→G)	R, G	Anti-inflammatory / anti-survival transcription	A common “hub” claim across propolis literature; contributes to reduced cytokine/pro-survival programs.
3	Intrinsic apoptosis (mitochondria → caspases)	↑ apoptosis; ↑ caspase activation (G)	↔ (usually less activation)	G	Cell death execution	Often downstream of sustained stress signaling and/or survival pathway suppression.
4	MAPK re-wiring (ERK / p38 / JNK)	Stress MAPK shifts; JNK/p38 often ↑ with stress (P→R); ERK variable	↔ / context-dependent	P, R, G	Signal reprogramming	MAPK directions depend on extract composition, dose, and tumor type; best described as “re-wiring” rather than fixed arrows for ERK.
5	PI3K → AKT (± mTOR)	↓ PI3K/AKT survival signaling (R→G)	↔	R, G	Growth/survival suppression	Often reported alongside reduced proliferation and increased apoptosis susceptibility.
6	Nrf2 / antioxidant response (HO-1, GSH enzymes)	Context-dependent (may be ↓ in tumor-stress settings; may be ↑ as adaptation)	Often ↑ protective antioxidant response under stress	R, G	Adaptive buffering	Nrf2 direction is not universal; avoid absolute “Nrf2 always ↑/↓” statements for propolis.
7	Angiogenesis (VEGF and related factors)	↓ angiogenic signaling outputs (G)	↔	G	Anti-angiogenic support	Usually shows up in later gene-expression / phenotype assays rather than early signaling.
8	EMT / invasion / migration (MMPs, EMT markers)	↓ EMT / ↓ migration & invasion programs (G)	↔	G	Anti-invasive phenotype	Often measured as reduced MMP activity and reduced migration/invasion phenotypes; timing tends to be later.
9	Antimicrobial / microbiome-relevant effects	Indirect (may reduce infection-driven inflammation)	Direct antimicrobial activity (context)	R, G	Host-protective / anti-infective	Propolis has documented antibacterial activity (stronger vs many Gram+ than Gram− in classic reports), which can matter for inflammation-linked biology.
10	Key bioactives (CAPE; flavonoids/phenolics)	CAPE-class compounds: tumor-selective cytotoxicity reported (G)	↔	G	“Active fraction” concept	Propolis is a mixture; effects may be driven by a few high-impact phenolics (e.g., CAPE) and vary by extract standardization.

Time-Scale Flag (TSF): P / R / G

P: 0–30 min (primary/physical–chemical effects; rapid signaling / phosphorylation shifts)
R: 30 min–3 hr (redox signaling + acute stress-response signaling)
G: >3 hr (gene-regulatory adaptation and phenotype-level outcomes)

NRF2, nuclear factor erythroid 2-related factor 2: Click to Expand ⟱

Source: TCGA

Type: Antiapoptotic

Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress. Thought of as "Master Regulator" of antioxidant response.
-One way to estimate Nrf2 induction is through the expression of NQO1.
NQO1, the most potent inducer:
SFN 0.2 μM,
quercetin (2.5 μM),
curcumin (2.7 μM),
Silymarin (3.6 μM),
tamoxifen (5.9 μM),
genistein (6.2 μM ),
beta-carotene (7.2μM),
lutein (17 μM),
resveratrol (21 μM),
indol-3-carbinol (50 μM),
chlorophyll (250 μM),
alpha-cryptoxanthin (1.8 mM),
and zeaxanthin (2.2 mM)

1. Raising Nrf2 enhances the cell's antioxidant defenses and ↓ROS. This strategy is used to decrease chemo-radio side effects.
2. Downregulating Nrf2 lowers antioxidant defenses and ↑ROS. In cancer cells this leads to DNA damage, and cell death.
3. However there are some cases where increasing Nrf2 paradoxically causes an increase in ROS (cancer cells). Such as cases of Mitochondial overload, signal crosstalk, reductive stress

-In some cases, Nrf2 is overexpressed in cancer cells, which can lead to the activation of genes involved in cell proliferation, angiogenesis, and metastasis. This can contribute to the development of resistance to chemotherapy and targeted therapies.
-Increased Nrf2 expression: Lung, Breast, Colorectal, Prostrate.
Decreased Nrf2 expression: Skine, Liver, Pancreatic.
-Nrf2 is a cytoprotective transcription factor which demonstrated both a negative effect as well as a positive effect on cancer
- "promotes Nrf2 translocation from the cytoplasm to the nucleus," means facilitates the movement of Nrf2 into the nucleus, thereby enhancing the cell's antioxidant and cytoprotective responses. -Major regulator of Nrf2 activity in cells is the cytosolic inhibitor Keap1.

Nrf2 Inhibitors and Activators
Nrf2 Inhibitors: Brusatol, Luteolin, Trigonelline, VitC, Retinoic acid, Chrysin
Nrf2 Activators: SFN, OPZ EGCG, Resveratrol, DATS, CUR, CDDO, Api
- potent Nrf2 inducers from plants include sulforaphane, curcumin, EGCG, resveratrol, caffeic acid phenethyl ester, wasabi, cafestol and kahweol (coffee), cinnamon, ginger, garlic, lycopene, rosemany

Nrf2 plays dual roles in that it can protect normal tissues against oxidative damage and can act as an oncogenic protein in tumor tissue.
– In healthy tissues, NRF2 activation helps protect cells from oxidative damage and maintains cellular homeostasis.
– In many cancers, constitutive activation of NRF2 (often through mutations in NRF2 itself or loss-of-function mutations in KEAP1) leads to an enhanced antioxidant capacity.
– This upregulation can promote tumor cell survival by enabling cancer cells to thrive under oxidative stress, resist chemotherapeutic agents, and sustain metabolic reprogramming.
– Elevated NRF2 levels have been implicated in promoting tumor growth, metastasis, and resistance to therapy in various malignancies.
– High or sustained NRF2 activity is frequently associated with aggressive tumor phenotypes, poorer prognosis, and decreased overall survival in several cancer types.
– While its activation is essential for protecting normal cells from oxidative stress, aberrant or sustained NRF2 activation in tumor cells can lead to enhanced survival, therapeutic resistance, and tumor progression.

NRF2 inhibitors: (to decrease antioxidant defenses and increase cell death from ROS).
-Brusatol: most cited natural inhibitors of Nrf2.
-Luteolin: luteolin can reduce Nrf2 activity in specific cancer models and may enhance cell sensitivity to chemotherapy. However, luteolin is also known as an antioxidant, and its influence on Nrf2 can sometimes be context dependent.
-Apigenin: certain studies to down‑regulate Nrf2 in cancer cells: Dose and context dependent .
-Oridonin:
-Wogonin: although its effects might be cell‑ and dose‑specific.
- Withaferin A

Scientific Papers found: Click to Expand⟱

2781-

CHr,

PBG,

Chrysin a promising anticancer agent: recent perspectives

Review,

Var,

PI3K↓, Akt↓, mTOR↓, MMP9↑, uPA↓, VEGF↓, AR↓, Casp↑, TumMeta↓, TumCCA↑, angioG↓, BioAv↓, *hepatoP↑, *neuroP↑, *SOD↑, *GPx↑, *ROS↓, *Inflam↓, *Catalase↑, *MDA↓, ROS↓, BBB↑, Half-Life↓, BioAv↑, ROS↑, eff↑, ROS↑, ROS↑, lipid-P↑, ER Stress↑, NOTCH1↑, NRF2↓, p‑FAK↓, Rho↓, PCNA↓, COX2↓, NF-kB↓, PDK1↓, PDK3↑, GLUT1↓, Glycolysis↓, mt-ATP↓, Ki-67↓, cMyc↓, ROCK1↓, TOP1↓, TNF-α↓, IL1β↓, CycB/CCNB1↓, CDK2↓, EMT↓, STAT3↓, PD-L1↓, IL2↑,

3252-

PBG,

Propolis Extract and Its Bioactive Compounds—From Traditional to Modern Extraction Technologies

Review,

NA,

*Inflam↓, *TNF-α↓, *NF-kB↓, *MAPK↓, *ERK↓, *antiOx↑, *NRF2↑, *cardioP↑, *Glycolysis↑, *Ca+2↓, *HO-1↑, *NRF2↑, *neuroP↑,

3251-

PBG,

The Antioxidant and Anti-Inflammatory Effects of Flavonoids from Propolis via Nrf2 and NF-κB Pathways

Review,

AD,

Review,

Diabetic,

Review,

Var,

in-vitro,

Nor,

H9c2

To induce oxidative stress, H9c2 cells were exposed to multiple H2O2 concentrations (0, 50, 100, 150, 200, and 250 μM) for 1 h

*antiOx↑, *Inflam↓, *ROS↓, *SOD↑, *Catalase↑, *HO-1↑, *NO↓, *NOS2↓, *NF-kB↓, *NRF2↑, *hepatoP↑, *MDA↓, *mtDam↓, *GSH↑, *p65↓, *TNF-α↓, *IL1β↓, *NRF2↑, *NRF2↓, *ROS⇅, *BioAv↓, *BioAv↑,

3253-

PBG,

Brazilian red propolis extract enhances expression of antioxidant enzyme genes in vitro and in vivo

in-vitro,

Nor,

HEK293

in-vivo,

Nor,

*NRF2↑, *ROS↓,

3254-

PBG,

Brazilian green propolis water extract up-regulates the early expression level of HO-1 and accelerates Nrf2 after UVA irradiation

in-vitro,

Nor,

Normal human skin fibroblast (NB1-RGB) cells

*HO-1↑, *NRF2↑,

3255-

PBG,

Propolis reversed cigarette smoke-induced emphysema through macrophage alternative activation independent of Nrf2

in-vivo,

Nor,

Eight-week-old male C57BL/6 mice

*IGF-1↓, *MMP2↑, *ROS↓, *Inflam↓, *IL10↓, *NRF2∅,

3257-

PBG,

The Potential Use of Propolis as a Primary or an Adjunctive Therapy in Respiratory Tract-Related Diseases and Disorders: A Systematic Scoping Review

Review,

Var,

CDK4↓, CDK6↓, pRB↓, ROS↓, TumCCA↑, P21↑, PI3K↓, Akt↓, EMT↓, E-cadherin↑, Vim↓, *COX2↓, *MPO↓, *MDA↓, *TNF-α↓, *IL6↓, *Catalase↑, *SOD↑, *AST↓, *ALAT↓, *IL1β↓, *IL10↓, *GPx↓, *TLR4↓, *Sepsis↓, *IFN-γ↑, *GSH↑, *NRF2↑, *α-SMA↓, *TGF-β↓, *IL5↓, *IL6↓, *IL8↓, *PGE2↓, *NF-kB↓, *MMP9↓,

1680-

PBG,

Protection against Ultraviolet A-Induced Skin Apoptosis and Carcinogenesis through the Oxidative Stress Reduction Effects of N-(4-bromophenethyl) Caffeamide, a Propolis Derivative

in-vitro,

Nor,

HS68

*ROS↓, *NRF2↑, *HO-1↑, *cJun↓, *MMP1↓, *MMP2↓, *p‑cJun↓, *cFos↓, *BAX↓, *Casp3↓, *DNAdam↓, *iNOS↓, *COX2↓, *IL6↓, *PGE2↓, *NO↓,

Showing Research Papers: 1 to 8 of 8

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 8

Pathway results for Effect on Cancer / Diseased Cells:

Clinical Biomarkers ⓘ

AR↓, 1, Ki-67↓, 1, PD-L1↓, 1,
Total Targets: 53

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

antiOx↑, 2, Catalase↑, 3, GPx↓, 1, GPx↑, 1, GSH↑, 2, HO-1↑, 4, MDA↓, 3, MPO↓, 1, NRF2↓, 1, NRF2↑, 8, NRF2∅, 1, ROS↓, 5, ROS⇅, 1, SOD↑, 3,

Mitochondria & Bioenergetics ⓘ

mtDam↓, 1,

Core Metabolism/Glycolysis ⓘ

ALAT↓, 1, Glycolysis↑, 1,

Cell Death ⓘ

BAX↓, 1, Casp3↓, 1, iNOS↓, 1, MAPK↓, 1,

Transcription & Epigenetics ⓘ

cJun↓, 1, p‑cJun↓, 1,

DNA Damage & Repair ⓘ

DNAdam↓, 1,

Proliferation, Differentiation & Cell State ⓘ

cFos↓, 1, ERK↓, 1, IGF-1↓, 1,

Migration ⓘ

Ca+2↓, 1, MMP1↓, 1, MMP2↓, 1, MMP2↑, 1, MMP9↓, 1, TGF-β↓, 1, α-SMA↓, 1,

Angiogenesis & Vasculature ⓘ

NO↓, 2,

Immune & Inflammatory Signaling ⓘ

COX2↓, 2, IFN-γ↑, 1, IL10↓, 2, IL1β↓, 2, IL5↓, 1, IL6↓, 3, IL8↓, 1, Inflam↓, 4, NF-kB↓, 3, p65↓, 1, PGE2↓, 2, TLR4↓, 1, TNF-α↓, 3,

Drug Metabolism & Resistance ⓘ

BioAv↓, 1, BioAv↑, 1,

Clinical Biomarkers ⓘ

ALAT↓, 1, AST↓, 1, IL6↓, 3, NOS2↓, 1,

Functional Outcomes ⓘ

cardioP↑, 1, hepatoP↑, 2, neuroP↑, 2,

Infection & Microbiome ⓘ

Sepsis↓, 1,
Total Targets: 58

Scientific Paper Hit Count for: NRF2, nuclear factor erythroid 2-related factor 2

8 Propolis -bee glue
1 Chrysin

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#:137  Target#:226  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

Propolis -bee glue / NRF2 Cancer Research Results

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Transcription & Epigenetics ⓘ

Protein Folding & ER Stress ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Hormonal & Nuclear Receptors ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Transcription & Epigenetics ⓘ

DNA Damage & Repair ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Infection & Microbiome ⓘ

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