Database Query Results : Betulinic acid, , TumCMig

BetA, Betulinic acid: Click to Expand ⟱

Features:

Betulinic acid "buh-TOO-li-nik acid" is a natural compound with antiretroviral, anti malarial, anti-inflammatory and anticancer properties. It is found in the bark of several plants, such as white birch, ber tree and rosemary, and has a complex mode of action against tumor cells.
-Betulinic acid is a naturally occurring pentacyclic triterpenoid
-vitro concentrations range from 1–100 µM, in vivo studies in rodents have generally used doses from 10–100 mg/kg
Precursor: Betulin, via oxidation at C-28
Lipophilicity: High (poor aqueous solubility)
-half-life reports vary 3-5 hrs?. Reported half-life varies by formulation and species; several studies report multi-hour systemic persistence.
BioAv -hydrophobic molecule with relatively poor water solubility.

Main Cancer action
-Direct mitochondrial targeting in cancer cells
-Minimal effect on normal cells

Key pathways
-Mitochondrial membrane permeabilization
-ROS-mediated apoptosis
-Caspase-independent death

Chemo relevance: Generally compatible, Not a redox buffer

Pathways:
- often induce ROS production
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓
- Lowers AntiOxidant defense in Cancer Cells(Often associated with reduced redox buffering capacity in tumor cells (e.g., GSH depletion); NRF2 direction model-dependent.): NRF2↓, SOD↓, GSH↓
- May Raise AntiOxidant defense in Normal Cells: NRF2↑, SOD↑, GSH↑, Catalase↑ Reports suggest relative sparing of normal cells and preservation of antioxidant capacity in some models
- lowers Inflammation : NF-kB↓(typ), COX2↓, p38↓ (context-dependent; often stress-activated), Pro-Inflammatory Cytokines : IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : , MMPs↓, MMP2↓, MMP9↓, TIMP2, IGF-1↓, VEGF↓, ROCK1↓, FAK↓, NF-κB↓, TGF-β↓, α-SMA↓, ERK↓
- reactivate genes thereby inhibiting cancer cell growth : P53↑, HSP↓(model-dependent), Sp proteins↓,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, CDK2↓, CDK4↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, FAK↓, ERK↓, EMT↓, TOP1↓,
- inhibits glycolysis (secondary to mitochondrial stress) ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, HK2↓, ECAR↓, GRP78↑(ER stress), GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓,
- inhibits Cancer Stem Cells in some studies : CSC↓, GLi1↓, β-catenin↓, OCT4↓,
- Others: PI3K↓(typ), AKT↓(typ), JAK↓, STAT↓, β-catenin↓, AMPK↓(AMPK is often activated during metabolic stress), ERK↓, JNK,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, 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	Intrinsic apoptosis (mitochondrial-mediated)	↑ mitochondria depolarization; ↑ cytochrome-c; ↑ caspase-9/3 activation	↔ limited activation (higher exposure required)	R, G	Execution of apoptosis	Betulinic acid (BA) is well known to engage the intrinsic apoptotic cascade, typically downstream of redox and signaling perturbations.
2	ROS / redox stress	↑ ROS (P→R)	↔ basal or antioxidant adaptation in some contexts	P, R	Stress induction	Many studies report ROS elevation in tumor cells exposed to BA; the direction and magnitude vary by cell type and exposure.
3	Mitochondrial permeability transition / ΔΨm loss	ΔΨm ↓ (R→G)	↔ maintained	R, G	Mitochondrial failure	Often observed as an early event preceding caspase activation in apoptosis studies.
4	PI3K / AKT / mTOR survival axis	↓ PI3K/AKT signaling; ↓ phospho-mTOR	↔	R, G	Survival/growth suppression	Betulinic acid often downregulates pro-survival kinase signaling, sensitizing cells to apoptosis and cytostasis.
5	NF-κB signaling	↓ NF-κB activity	↔	R, G	Pro-survival/inflammatory transcription suppression	Reduction in NF-κB activity limits pro-survival gene expression; supports sensitization to stressors.
6	MAPK re-wiring (JNK / ERK / p38)	Stress-MAPK shifts; JNK/p38 often ↑; ERK context-dependent	↔	P, R	Early stress signaling	MAPK responses vary by model, with stress-associated p38/JNK often activated and ERK modulation variable.
7	Cell-cycle checkpoints (p21, p27, cyclins)	↑ p21/p27; ↑ G1/S or G2/M arrest	↔	G	Proliferation arrest	BA often induces cell-cycle blockade, slowing proliferation before apoptosis commitment.
8	Angiogenic signaling (VEGF & related)	↓ VEGF; anti-angiogenic outputs	↔	G	Anti-angiogenic support	Typically seen at the level of reduced pro-angiogenic factor expression or secretion in longer-term assays.
9	EMT / invasion / migration programs (MMPs)	↓ MMP2/MMP9; ↓ migration/invasion	↔	G	Anti-invasive phenotype	Often measured as reduced invasive capacity and decreased expression of EMT markers in later time points.
10	Autophagy modulation	↑ LC3-II; ↑ autophagic flux (model dependent)	↔	G	Adaptive clearance / cell fate shift	BA can modulate autophagy, which may either sensitize cells to death pathways or reflect adaptive stress responses.

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

P: 0–30 min (primary/physical-chemical effects; rapid kinase/redox signaling)
R: 30 min–3 hr (acute redox and stress-response activation)
G: >3 hr (gene-regulatory adaptation and phenotypic outcomes)

TumCMig, Tumor cell migration: Click to Expand ⟱

Source:

Type:

Tumor cell migration is a critical process in cancer progression and metastasis, which is the spread of cancer cells from the primary tumor to distant sites in the body.

Scientific Papers found: Click to Expand⟱

2742-

BetA,

Betulinic acid impairs metastasis and reduces immunosuppressive cells in breast cancer models

in-vitro,

BC,

MDA-MB-231

in-vivo,

BC,

4T1

intraperitoneal administration of 10 mg/kg/day BA

in-vitro,

BC,

MCF-7

tumCV↓, BA decreased the viability of three breast cancer cell lines and markedly impaired cell migration and invasion
TumCMig↓,
TumCI↓,
STAT3↑, BA could inhibit the activation of stat3 and FAK which resulted in a reduction of matrix metalloproteinases (MMPs)
FAK↓,
MMPs↓,
MMP2↓, BA treatment decreased the expression of MMP-2 and MMP-9 while increased the expression of TIMP-2 in 4T1 and MDA-MB-231 cells.
MMP9↓,
TIMP2↑,

2741-

BetA,

Betulinic acid triggers apoptosis and inhibits migration and invasion of gastric cancer cells by impairing EMT progress

in-vitro,

GC,

SNU16

in-vitro,

GC,

NCI-N87

in-vivo,

NA,

(40 mg/kg)

mice

TumCG↓, BA had significant cytotoxic and inhibitory effects on GC cells in a dose- and time-dependent manner.
TumCMig↓, BA inhibited the migratory and invasive abilities of SNU-16 cells
TumCI↓,
N-cadherin↓, relative expression level of N-cadherin in SNU-16 cells was drastically down-regulated, and the expression of E-cadherin in SNU-16 cells was distinctly up-regulated in comparison to that in the control group, implying a break in the EMT process.
E-cadherin↑,
EMT↓,
Ki-67↓, proportions of Ki-67-positive and MMP2-positive cells were significantly lower in the tumour sections of the BA-treated group than those in the sections of the control group
MMP2↓,

2756-

BetA,

Betulinic acid inhibits growth of hepatoma cells through activating the NCOA4-mediated ferritinophagy pathway

in-vitro,

HCC,

HUH7

10 μM was selected as a low dose (BETL group), 20 μM as a medium dose (BETM group) and 40 μM as a high dose (BETH group)

in-vitro,

HCC,

H1299

TumCP↓, betulinic acid could suppress proliferation and migration of hepatoma cells, raised ROS level and inhibited antioxidation level in cells
ROS↓,
antiOx↓,
TumCG↓, These findings indicate that betulinic acid has the capacity to significantly impede hepatoma cells growth and migration
TumCMig↓,
NRF2↓, The expression of antioxidant proteins Nrf2, GPX4 and HO-1 was also considerably lower in the BETM and BETH groups than in the Control group
GPx4↓,
HO-1↓,
NCOA4↑, suggesting that betulinic acid activates ferritinophagy by boosting NCOA4 expression and FTH1 degradation.
FTH1↓, betulinic acid groups (10 mg/kg, 20 mg/kg, and 40 mg/kg) greatly boosted LC3II and NCOA4 expressions and suppressed FTH1
Ferritin↑, In summation, betulinic acid decreases antioxidation in tumour tissues from nude mice, inhibits ferritin expression, enhances the expression of ferritinophagy-associated protein, activates ferritinophagy, and initiates ferroptosis in tumour cells.
Ferroptosis↑,
GSH↓, In comparison to the Control group, the betulinic acid groups (10 mg/kg, 20 mg/kg and 40 mg/kg) reduced dramatically GSH and hydroxyl radical inhibition capacity in serum, considerably increased serum Fe2+), and decreased dramatically serum MDA
MDA↓,

2757-

BetA,

Betulinic Acid Inhibits Glioma Progression by Inducing Ferroptosis Through the PI3K/Akt and NRF2/HO-1 Pathways

in-vitro,

GBM,

U251

tumCV↓, BA reduced viability; inhibited colony formation, migration, and invasion; and triggered apoptosis.
TumCMig↓,
TumCI↓,
Apoptosis↑,
p‑PI3K↓, BA administration decreased the levels of phosphorylated PI3K and AKT.
p‑Akt↓,
Ferroptosis↑, BA-induced ferroptosis and HO-1 and NRF2 levels were increased
HO-1↑,
NRF2↑,

2719-

BetA,

Betulinic Acid Restricts Human Bladder Cancer Cell Proliferation In Vitro by Inducing Caspase-Dependent Cell Death and Cell Cycle Arrest, and Decreasing Metastatic Potential

in-vitro,

CRC,

T24/HTB-9

30 μg/mL BA for 48 h

in-vitro,

Bladder,

UMUC3

33.2 μg/mL

in-vitro,

Bladder,

5637

 28.5 μg/mL

TumCD↑, BA induced cell death in bladder cancer cells and that are accompanied by apoptosis, necrosis, and cell cycle arrest.
Apoptosis↑,
TumCCA↑,
CycB/CCNB1↓, BA decreased the expression of cell cycle regulators, such as cyclin B1, cyclin A, cyclin-dependent kinase (Cdk) 2, cell division cycle (Cdc) 2, and Cdc25c
cycA1/CCNA1↓,
CDK2↓,
CDC25↓,
mtDam↑, BA-induced apoptosis was associated with mitochondrial dysfunction that is caused by loss of mitochondrial membrane potential, which led to the activation of mitochondrial-mediated intrinsic pathway.
BAX↑, BA up-regulated the expression of Bcl-2-accociated X protein (Bax) and cleaved poly-ADP ribose polymerase (PARP), and subsequently activated caspase-3, -8, and -9.
cl‑PARP↑,
Casp3↑,
Casp8↑,
Casp9↑,
Snail↓, decreased the expression of Snail and Slug in T24 and 5637 cells, and matrix metalloproteinase (MMP)-9 in UMUC-3 cells.
Slug↓,
MMP9↓,
selectivity↑, Among the bladder cancer cell lines, 5637 cells were much more sensitive to BA than T24 or UMUC-3 cells under the same conditions. However, BA does not affect cell growth in normal cell lines including RAW 264.7
MMP↓, BA Induces Loss of Mitochondrial Membrane Potential (MMP, ΔΨm) in Human Bladder Cancer Cells
ROS∅, As a result, we found that BA did not affect intracellular ROS levels in all three bladder cancer cells. In addition, BA-induced cell viability inhibition was not restored by NAC pre-treatment
TumCMig↓, BA Decreases Migration and Invasion of Human Bladder Cancer Cells
TumCI↓,

2730-

BetA,

Betulinic acid induces autophagy-dependent apoptosis via Bmi-1/ROS/AMPK-mTOR-ULK1 axis in human bladder cancer cells

in-vitro,

Bladder,

T24/HTB-9

tumCV↓, The present study showed that BA exposure significantly suppressed viability, proliferation, and migration of EJ and T24 human bladder cancer cells
TumCP↓,
TumCMig↓,
Casp↑, These effects reflected caspase 3-mediated apoptosis
TumAuto↑, BA-induced autophagy was evidenced by epifluorescence imaging of lentivirus-induced expression of mCherry-GFP-LC3B and increased expression of two autophagy-related proteins, LC3B-II and TEM.
LC3B-II↑,
p‑AMPK↑, Moreover, enhanced AMPK phosphorylation and decreased mTOR and ULK-1 phosphorylation suggested BA activates autophagy via the AMPK/mTOR/ULK1 pathway.
mTOR↓,
BMI1↓, decreased Bmi-1 expression in BA-treated T24 cell xenografts in nude mice suggested that downregulation of Bmi-1 is the underlying mechanism in BA-mediated, autophagy-dependent apoptosis.
ROS↑, BA induced ROS production dose-dependently
eff↓, Co-incubation with NAC effectively blocked ROS production (Figure 4B), rescued cell viability,

2738-

BetA,

Betulinic Acid Suppresses Breast Cancer Metastasis by Targeting GRP78-Mediated Glycolysis and ER Stress Apoptotic Pathway

in-vitro,

BC,

MDA-MB-231

in-vitro,

BC,

BT549

in-vivo,

NA,

mice

TumCI↓, BA inhibited invasion and migration of highly aggressive breast cancer cells.
TumCMig↓,
Glycolysis↓, Moreover, BA could suppress aerobic glycolysis of breast cancer cells presenting as a reduction of lactate production, quiescent energy phenotype transition, and downregulation of aerobic glycolysis-related proteins.
lactateProd↓, lactate production in both MDA-MB-231 and BT-549 cells was significantly reduced following BA administration
GRP78/BiP↑, (GRP78) was also identified as the molecular target of BA in inhibiting aerobic glycolysis. BA treatment led to GRP78 overexpression, and GRP78 knockdown abrogated the inhibitory effect of BA on glycolysis.
ER Stress↑, Further studies demonstrated that overexpressed GRP78 activated the endoplasmic reticulum (ER) stress sensor PERK.
PERK↑,
p‑eIF2α↑, Subsequent phosphorylation of eIF2α led to the inhibition of β-catenin expression, which resulted in the inhibition of c-Myc-mediated glycolysis.
β-catenin/ZEB1↓,
cMyc↓, These findings suggested that BA inhibited the β-catenin/c-Myc pathway by interrupting the binding between GRP78 and PERK and ultimately suppressed the glycolysis of breast cancer cells.
ROS↑, (i) the induction of cancer cell apoptosis via the mitochondrial pathway induced by the release of soluble factors or generation of reactive oxygen species (ROS)
angioG↓, (ii) the inhibition of angiogenesis [24];
Sp1/3/4↓, (iii) the degradation of transcription factor specificity protein 1 (Sp1)
DNAdam↑, (iv) the induction of DNA damage by suppressing topoisomerase I
TOP1↓,
TumMeta↓, BA Inhibits Metastasis of Highly Aggressive Breast Cancer Cells
MMP2↓, BA significantly decreased the expression of MMP-2 and MMP-9 secreted by breast cancer cells
MMP9↓,
N-cadherin↓, BA downregulated the levels of N-cadherin and vimentin as the mesenchymal markers, while increased E-cadherin which is an epithelial marker (Figure 2(c)), validating the EMT inhibition effects of BA in breast cancer cells.
Vim↓,
E-cadherin↑,
EMT↓,
LDHA↓, the levels of glycolytic enzymes, including LDHA and p-PDK1/PDK1, were all decreased in a dose-dependent manner by BA
p‑PDK1↓,
PDK1↓,
ECAR↓, extracellular acidification rate (ECAR), which reflects the glycolysis activity, was retarded following BA administration.
OCR↓, oxygen consumption rate (OCR), which is a marker of mitochondrial respiration, was also decreased simultaneously
Hif1a↓, BA could reduce prostate cancer angiogenesis via inhibiting the HIF-1α/stat3 pathway [39]
STAT3↓,

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 7

Pathway results for Effect on Cancer / Diseased Cells:

Clinical Biomarkers ⓘ

Ferritin↑, 1, Ki-67↓, 1,
Total Targets: 80

Pathway results for Effect on Normal Cells:

Total Targets: 0

Scientific Paper Hit Count for: TumCMig, Tumor cell migration

7 Betulinic acid

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#:42  Target#:326  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

Database Query Results : Betulinic acid, , TumCMig

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Metal & Cofactor Biology ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Kinase & Signal Transduction ⓘ

Transcription & Epigenetics ⓘ

Protein Folding & ER Stress ⓘ

Autophagy & Lysosomes ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Pathway results for Effect on Normal Cells:

Home Page