Berberine / Hif1a Cancer Research Results

BBR, Berberine: Click to Expand ⟱

Features:

Berberine — Berberine is a protoberberine/isoquinoline alkaloid natural product found in plants such as Coptis, Berberis, and Phellodendron. It is a small-molecule phytochemical with pleiotropic metabolic, anti-inflammatory, and anticancer signaling effects rather than a single highly selective target profile. Its standard abbreviation is BBR. In oncology it is best classified as a multitarget natural-product lead compound and adjunct-sensitizer candidate, with strong preclinical evidence but no established standard anticancer regulatory use. Its translational profile is shaped by very low conventional oral bioavailability, extensive first-pass metabolism, broad tissue distribution, and substantial context dependence between cancer-cell pro-death effects and normal-cell cytoprotective redox effects.

Primary mechanisms (ranked):

AMPK-centered metabolic stress with mitochondrial dysfunction, ATP depletion, and apoptosis/autophagy induction
Suppression of aerobic glycolysis and hypoxia signaling, including HIF-1α, GLUT1, HK2, LDHA, and PKM2-linked tumor metabolism
Anti-proliferative cell-cycle control with cyclin/CDK suppression and tumor suppressor reactivation
Inhibition of PI3K/AKT, MAPK/ERK, JAK/STAT, and NF-κB inflammatory-survival signaling
Anti-metastatic and anti-EMT activity via Wnt/β-catenin, TGF-β/Smad, FAK/RhoA/ROCK, MMPs, and CXCR4-related programs
Pro-oxidant mitochondrial ROS elevation and ER-stress/caspase signaling in many cancer models, with opposite antioxidant/NRF2-supportive effects in some normal-cell and non-cancer settings
Context-dependent chemosensitization and radiosensitization, including effects on hypoxia signaling and DNA-repair competence
Emerging ferroptosis-related activity in some tumor models, but not a universal dominant mechanism across berberine biology

Bioavailability / PK relevance: Conventional oral berberine has poor systemic bioavailability, often cited as below 1% in animal studies, because of limited absorption, P-glycoprotein efflux, first-pass intestinal/hepatic metabolism, and self-aggregation. Human exposure is usually in the low ng/mL plasma range with conventional dosing, while multiple metabolites may contribute to activity. Tissue distribution can exceed plasma levels, but PK remains a major clinical translation constraint.

In-vitro vs systemic exposure relevance: Many anticancer in-vitro studies use roughly 10–100 µM, commonly around 20–50 µM, which usually exceeds readily achievable conventional plasma exposure after standard oral dosing. Therefore, direct translation of cell-culture potency to systemic monotherapy expectations is limited unless local gut exposure, tissue accumulation, metabolite contribution, formulation enhancement, or combination use is specifically relevant.

Clinical evidence status: Strong preclinical and mechanistic evidence; limited early human oncology/chemoprevention evidence; no established phase III anticancer efficacy standard and no mainstream regulatory approval as an anticancer drug. Current clinical relevance is best viewed as investigational and adjunct-oriented rather than proven standalone oncology therapy.

Berberine is a chemical found in some plants like European barberry, goldenseal, goldthread, Oregon grape, phellodendron, and tree turmeric. Berberine is a bitter-tasting and yellow-colored chemical.
Coptis (commonly referring to Coptidis Rhizoma, a traditional Chinese medicinal herb) contains bioactive alkaloids (most notably berberine and coptisine) that have been studied for their pharmacological effects—including their influence on reactive oxygen species (ROS) and related pathways.

– Berberine is known for its relatively low oral bioavailability, often cited at less than 1%. This low bioavailability is mainly due to poor intestinal absorption and active efflux by transport proteins such as P-glycoprotein.
– Despite the low bioavailability, berberine is still pharmacologically active, and its metabolites may also contribute to its overall effects.

• Effective Dosage in Studies
– Many clinical trials or preclinical studies use dosages in the range of 500 to 1500 mg per day, typically administered in divided doses.
– Therefore, to obtain a bioactive dose of berberine, supplementation in a standardized extract form is necessary.

-IC50 in cancer cell lines: Approximately 10–100 µM (commonly around 20–50 µM in many models)
-IC50 in normal cell lines: Generally higher (often above 100 µM), although this can vary with cell type
- In vivo studies: Dosing regimens in animal models generally range from about 50 to 200 mg/kg
- very effective AChE inhibitor (Alzheimers)
- Berberine may enhance the effects of blood-thinning medications like warfarin and aspirin.

-Note half-life reports vary 2.5-90hrs?.
-low solubility of apigenin in water : BioAv
Pathways:
- induce ROS production
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, UPR↑, cl-PARP↑, HSP↓
- Lowers AntiOxidant defense in Cancer Cells: NRF2↓, GSH↓
- Raises AntiOxidant defense in Normal Cells: NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- PI3K/AKT(Inhibition), JAK/STATs, Wnt/β-catenin, AMPK, MAPK/ERK, and JNK.
- inhibit Growth/Metastases : , MMPs↓, MMP2↓, MMP9↓, IGF-1↓, uPA↓, VEGF↓, ROCK1↓, FAK↓, RhoA↓, NF-κB↓, CXCR4↓, TGF-β↓, α-SMA↓, ERK↓
- reactivate genes thereby inhibiting cancer cell growth : HDAC↓, DNMT1↓, EZH2↓, P53↑, HSP↓
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, FAK↓, ERK↓,
- inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, Glucose↓, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, Notch↓, FGF↓, PDGF↓, EGFR↓, Integrins↓,
- inhibits Cancer Stem Cells : CSC↓, Hh↓, GLi1↓, CD133↓, β-catenin↓, n-myc↓, sox2↓, notch2↓, nestin↓, OCT4↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK↓, α↓, 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 / Target Axis	Direction	Primary Effect	Notes / Cancer Relevance	Ref
1	AMPK → mTOR axis	↑ AMPK / ↓ mTOR signaling	Metabolic stress + growth suppression	In vivo/in vitro colon tumorigenesis model: berberine activates AMPK, inhibits mTOR signaling and reduces proliferation/tumorigenesis, growth suppression, autophagy, HIF-1α ↓, glycolysis ↓, berberine’s known mitochondrial/energetic effects	(ref)
2	Mitochondrial dysfunction / ROS generation	↑ ROS / mitochondrial stress	Upstream metabolic trigger	Berberine inhibits mitochondrial function, increases ROS, and contributes to AMPK activation and downstream apoptosis	(ref)
3	Mitochondrial apoptosis (cytochrome c release)	↑ cytochrome c release	Intrinsic death signaling	Oral cancer model: berberine reduces mitochondrial membrane potential, releases cytochrome c, activates caspase-3	(ref)
4	Intrinsic apoptosis (caspase-3 activation)	↑ caspase-3 activation	Programmed cell death	Same oral cancer study documents caspase-3 activation as a key execution marker	(ref)
5	NF-κB signaling (p65 activation)	↓ NF-κB activation	Reduced pro-survival transcription	Colon cancer model reports inhibition of p65 phosphorylation; interpreted as secondary to metabolic/redox stress	(ref)
6	Cell cycle control	↑ G1 arrest	Proliferation blockade	Prostate cancer model: berberine induces G1-phase cell cycle arrest and caspase-3–dependent apoptosis	(ref)
7	Hypoxia / glycolysis signaling (HIF-1α)	↓ HIF-1α protein	Warburg / glycolysis suppression	Berberine suppresses mTOR and reduces HIF-1α protein expression downstream of AMPK activation	(ref)
8	Angiogenesis signaling (HIF-1α → VEGF axis)	↓ VEGF signaling	Reduced vascular support	Lung cancer study: berberine suppresses VEGF signaling alongside HIF-1α inhibition	(ref)
9	PI3K–AKT–mTOR signaling	↓ PI3K / AKT / mTOR	Survival pathway suppression	Gastric cancer paper: berberine represses PI3K/AKT/mTOR signaling and improves chemosensitivity	(ref)
10	Migration / invasion programs	↓ migration & invasion	Anti-metastatic phenotype	Tongue SCC model: berberine suppresses migration and invasion with associated signaling changes	(ref)
11	Telomerase (hTERT) / immortalization axis	↓ hTERT-related signaling	Reduced proliferative capacity	Lung cancer study includes AP-2/hTERT regulatory axis modulation by berberine	(ref)
12	In vivo tumor suppression	↓ tumorigenesis	Demonstrated anti-tumor effect	Colon tumorigenesis model confirms reduced proliferation and tumor burden with berberine	(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⟱

2709-

BBR,

Berberine inhibits the glycolysis and proliferation of hepatocellular carcinoma cells by down-regulating HIF-1α

in-vitro,

HCC,

HepG2

0, 50, 100, or 200 μmol/

TumCP↓, TumCMig↓, TumCI↓, Apoptosis↑, Glycolysis↓, Hif1a↓, GLUT1↓, HK2↓, PKM2↓, LDHA↓,

2708-

BBR,

Berberine decelerates glucose metabolism via suppression of mTOR‑dependent HIF‑1α protein synthesis in colon cancer cells

in-vitro,

CRC,

HCT116

 0, 6.25, 12.5, 25, 50 and 100 µM of berberine for 24 or 15 h

TumCG↓, GlucoseCon↓, GLUT1↓, LDHA↓, HK2↓, Hif1a↓, mTOR↓, Glycolysis↓,

2695-

BBR,

The effects of Berberis vulgaris consumption on plasma levels of IGF-1, IGFBPs, PPAR-γ and the expression of angiogenic genes in women with benign breast disease: a randomized controlled clinical trial

Trial,

BC,

85 eligible patients diagnosed with benign breast disease.

IGF-1↓, PPARγ↓, VEGF↓, Hif1a↓, angioG↓,

2686-

BBR,

Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and microRNAs

Review,

Nor,

Inflam↓, IL6↓, MCP1↓, COX2↓, PGE2↓, MMP2↓, MMP9↓, DNAdam↑, eff↝, Telomerase↓, Bcl-2↓, AMPK↑, ROS↑, MMP↓, ATP↓, p‑mTORC1↓, p‑S6K↓, ERK↓, PI3K↓, PTEN↑, Akt↓, Raf↓, MEK↓, Dose↓, Dose↑, selectivity↑, TumCCA↑, eff↑, EGFR↓, Glycolysis↓, Dose?, p27↑, CDK2↓, CDK4↓, cycD1/CCND1↓, cycE/CCNE↓, Bax:Bcl2↑, Casp3↑, Casp9↑, VEGFR2↓, ChemoSen↑, eff↑, eff↑, PGE2↓, JAK2↓, STAT3↓, CXCR4↓, CCR7↓, uPA↓, CSCs↓, EMT↓, Diff↓, CD133↓, Nestin↓, n-MYC↓, NOTCH↓, SOX2↓, Hif1a↓, VEGF↓, RadioS↑,

5180-

BBR,

Berberine Targets AP-2/hTERT, NF-κB/COX-2, HIF-1α/VEGF and Cytochrome-c/Caspase Signaling to Suppress Human Cancer Cell Growth

in-vitro,

NSCLC,

100 µM BBR

TumCMig↓, TumCP↓, Apoptosis↑, TFAP2A↓, hTERT/TERT↓, NF-kB↓, COX2↓, Hif1a↓, VEGF↓, Akt↓, p‑ERK↓, Cyt‑c↑, cl‑Casp↑, cl‑PARP↑, PI3K↓, Akt↓, Raf↓, MEK↓, ERK↓,

5179-

BBR,

Regulation of Cell Signaling Pathways by Berberine in Different Cancers: Searching for Missing Pieces of an Incomplete Jig-Saw Puzzle for an Effective Cancer Therapy

Review,

Var,

AMPK↑, Casp3↑, cl‑PARP↑, Mcl-1↓, cFLIP↓, β-catenin/ZEB1↓, Wnt↓, STAT3↓, mTOR↓, Hif1a↓, NF-kB↓, SIRT1↑, DNMT1↓, DNMT3A↓, miR-29b↓, IGFBP1↑, eff↑, chemoPv↑, BioAv↓,

1392-

BBR,

Based on network pharmacology and experimental validation, berberine can inhibit the progression of gastric cancer by modulating oxidative stress

in-vitro,

GC,

AGS

2.5, 5, 10, 20, 40 µM

in-vitro,

GC,

MKN45

TumCG↓, TumCMig↓, ROS↑, MDA↑, SOD↓, NRF2↓, HO-1↓, Hif1a↓, EMT↓, Snail↓, Vim↓,

956-

BBR,

Berberine inhibits HIF-1alpha expression via enhanced proteolysis

in-vitro,

Nor,

HUVECs

7.5uM/16hr

mice

in-vitro,

GC,

SCM1

Hif1a↓, angioG↓,

1399-

BBR,

Rad,

Radiotherapy Enhancing and Radioprotective Properties of Berberine: A Systematic Review

Review,

NA,

*ROS↓, *MDA↓, *TNF-α↓, *TGF-β↓, *IL10↑, ROS↑, DNAdam↑, mtDam↑, MMP↓, Apoptosis↑, TumCCA↑, Hif1a↓, VEGF↓, RadioS↑,

Showing Research Papers: 1 to 9 of 9

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 9

Pathway results for Effect on Cancer / Diseased Cells:

Functional Outcomes ⓘ

chemoPv↑, 1,
Total Targets: 99

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

MDA↓, 1, ROS↓, 1,

Migration ⓘ

TGF-β↓, 1,

Immune & Inflammatory Signaling ⓘ

IL10↑, 1, TNF-α↓, 1,
Total Targets: 5

Scientific Paper Hit Count for: Hif1a, HIF1α/HIF1a

9 Berberine
1 Radiotherapy/Radiation

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#:41  Target#:143  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

Berberine / Hif1a Cancer Research Results

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Migration ⓘ

Immune & Inflammatory Signaling ⓘ

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