Database Query Results : Betulinic acid, , EMT

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 : EMT↓, 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)
EMT, Epithelial-Mesenchymal Transition: Click to Expand ⟱
Source:
Type:
Biological process in which epithelial cells lose their cell polarity and cell-cell adhesion properties and gain mesenchymal traits, such as increased motility and invasiveness. This process is pivotal during embryogenesis and wound healing. Hh signaling pathway is able to regulate the EMT. Snail, E-cadherin and N-cadherin, key components of EMT; EMT-related factors, E-cadherin, N-cadherin, vimentin; The hallmark of EMT is the upregulation of N-cadherin followed by the downregulation of E-cadherin.
EMT is regulated by various signaling pathways, including TGF-β, Wnt, Notch, and Hedgehog pathways. Transcription factors such as Snail, Slug, Twist, and ZEB play critical roles in repressing epithelial markers (like E-cadherin) and promoting mesenchymal markers (like N-cadherin and vimentin).
EMT is associated with increased tumor aggressiveness, enhanced migratory and invasive capabilities, and resistance to apoptosis.
Scientific Papers found: Click to Expand⟱
2743- BetA,    Betulinic acid and the pharmacological effects of tumor suppression
- Review, Var, NA
ROS↓, BA improves the level of reactive oxygen species (ROS) production and alters the mitochondrial membrane potential gradient, followed by the release of cytochrome c (Cyt c), which causes the mitochondrial-mediated apoptosis of tumor cells via a caspas
MMP↓,
Cyt‑c↑,
Apoptosis↑,
TumCCA↑, BA can inhibit cancer cell growth and proliferation via cell cycle arrest
Sp1/3/4↓, BA, can inhibit the protein expression of Sp1, Sp2 and Sp4 through the microRNA (miR)-27a-ZBTB10-Sp1 axis
STAT3↓, BA can downregulate the activation of STAT3 through the upregulation of Src homology 2 domain-containing phosphatase 1 (SHP-1)
NF-kB↓, NF-κB can be inhibited by reducing the activation of inhibitor of NF-κB (IκBα) kinase (IKKβ) and phosphorylation of IκBα with BA
EMT↓, nvasion and metastasis of malignancies is prevented via epithelial-mesenchymal transition (EMT) and inhibition of topoisomerase I
TOP1↓,
MAPK↑, BA leads to the activation, via phosphorylation, of pro-apoptotic MAPK proteins, P38 and SAP/JNK, the formation of ROS and the upregulation of caspase
p38↑,
JNK↑,
Casp↑,
Bcl-2↓, BA downregulates Bcl-2 and upregulates the Bax gene in HeLa cell lines
BAX↑,
VEGF↓, BA can decrease the expression of VEGF via Sp proteins, thus having an antiangiogenic role
LAMs↓, BA suppresses the expression of lamin B1 in pancreatic cancer cells

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, NA
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↓,

2729- BetA,    Betulinic acid in the treatment of tumour diseases: Application and research progress
- Review, Var, NA
ChemoSen↑, Betulinic acid can increase the sensitivity of cancer cells to other chemotherapy drugs
mt-ROS↑, BA has antitumour activity, and its mechanisms of action mainly include the induction of mitochondrial oxidative stress
STAT3↓, inhibition of signal transducer and activator of transcription 3 and nuclear factor-κB signalling pathways.
NF-kB↓,
selectivity↑, A main advantage of BA and its derivatives is that they are cytotoxic to different human tumour cells, while cytotoxicity is much lower in normal cells.
*toxicity↓, It can kill cancer cells but has no obvious effect on normal cells and is also nontoxic to other organs in xenograft mice at a dose of 500 mg/kg
eff↑, BA combined with chemotherapy drugs, such as platinum and mithramycin A, can induce apoptosis in tumour cells
GRP78/BiP↑, In animal xenograft tumour models, BA enhanced the expression of glucose-regulated protein 78 (GRP78)
MMP2↓, reduced the levels of matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, in lung metastatic lesions of breast cancer, indicating that BA can reduce the invasiveness of breast cancer in vivo and block epithelial mesenchymal transformation (EMT
P90RSK↓,
TumCI↓,
EMT↓,
MALAT1↓, MALAT1, a lncRNA, was downregulated in hepatocellular carcinoma (HCC) cells treated with BA in vivo,
Glycolysis↓, Suppressing aerobic glycolysis of cancer cells by GRP78/β-Catenin/c-Myc signalling pathways
AMPK↑, activating AMPK signaling pathway
Sp1/3/4↓, inhibiting Sp1. BA at 20 mg/kg/d, the tumour volume and weight were significantly reduced, and the expression levels of Sp1, Sp3, and Sp4 in tumour tissues were lower than those in control mouse tissues
Hif1a↓, Suppressing the hypoxia-induced accumulation of HIF-1α and expression of HIF target genes
angioG↓, PC3: Having anti-angiogenesis effect
NF-kB↑, LNCaP, DU145 — Inducing apoptosis and NF-κB pathway
NF-kB↓, U266 — Inhibiting NF-κB pathway.
MMP↓, BA produces ROS and reduces mitochondrial membrane potential; the mitochondrial permeability transition pore of the mitochondrial membrane plays an important role in apoptosis signal transduction.
Cyt‑c↑, Mitochondria release cytochrome C and increase the levels of Caspase-9 and Caspase-3, inducing cell apoptosis.
Casp9↑,
Casp3↑,
RadioS↑, BA could be a promising drug for increasing radiosensitization in oral squamous cell carcinoma radiotherapy.
PERK↑, BA treatment increased the activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) apoptosis pathway and decreased the expression of Sp1.
CHOP↑,
*toxicity↓, BA at a concentration of 50 μg/ml did not inhibit the growth of normal peripheral blood lymphocytes, indicating that the toxicity of BA was at least 1000 times less than that of doxorubicin

2731- BetA,    Betulinic Acid for Glioblastoma Treatment: Reality, Challenges and Perspectives
- Review, GBM, NA - Review, Park, NA - Review, AD, NA
BBB↑, Notably, its ability to cross the blood–brain barrier addresses a significant challenge in treating neurological pathologies.
*GSH↑, BA can also dramatically reduce catalepsy and stride length, while increasing the brain’s dopamine content, glutathione activity, and catalase activity in hemiparkinsonian rats
*Catalase↑,
*motorD↑,
*neuroP↑, in Alzheimer’s disease rat models, it can improve neurobehavioral impairments . BA has exhibited great neuroprotective properties.
*cognitive↑, BA improves cognitive ability and neurotransmitter levels, and protects from brain damage by lowering reactive oxygen species (ROS) levels
*ROS↓,
*antiOx↑, enhancing brain tissue’s antioxidant capacity, and preventing the release of inflammatory cytokines
*Inflam↓,
MMP↓, BA can decrease the mitochondrial outer membrane potential (MOMP)
STAT3↓, The compound can inhibit the signal transducer and activator of transcription (STAT) 3 signaling pathways, involved in differentiation, proliferation, apoptosis, metastasis formation, angiogenesis, and metabolism, and the NF-kB signaling pathway,
NF-kB↓,
Sp1/3/4↓, BA has shown an ability to control cancer growth through the modulation of Sp transcription factors, inhibit DNA topoisomerase
TOP1↓,
EMT↓, inhibit the epithelial-to-mesenchymal transition (EMT)
Hif1a↓, BA has also been associated with an antiangiogenic response under hypoxia conditions, through the STAT3/hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) signaling pathway
VEGF↓,
ChemoSen↑, BA has shown great potential as an adjuvant to therapy since its use combined with standard treatment of chemotherapy and irradiation can enhance their cytotoxic effect on cancer cells
RadioS↑,
BioAv↓, Despite having great potential as a therapeutic agent, it is hard for BA to fulfill the requirements for adequate water solubility, maintaining both significant cytotoxicity and selectivity for tumor cells.

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, NA
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: 5

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

ROS↓, 1,   ROS↑, 1,   mt-ROS↑, 1,  

Mitochondria & Bioenergetics ⓘ

MMP↓, 3,   OCR↓, 1,  

Core Metabolism/Glycolysis ⓘ

AMPK↑, 1,   cMyc↓, 1,   ECAR↓, 1,   Glycolysis↓, 2,   lactateProd↓, 1,   LDHA↓, 1,   PDK1↓, 1,   p‑PDK1↓, 1,  

Cell Death ⓘ

Apoptosis↑, 1,   BAX↑, 1,   Bcl-2↓, 1,   Casp↑, 1,   Casp3↑, 1,   Casp9↑, 1,   Cyt‑c↑, 2,   JNK↑, 1,   MAPK↑, 1,   p38↑, 1,  

Kinase & Signal Transduction ⓘ

Sp1/3/4↓, 4,  

Protein Folding & ER Stress ⓘ

CHOP↑, 1,   p‑eIF2α↑, 1,   ER Stress↑, 1,   GRP78/BiP↑, 2,   PERK↑, 2,  

DNA Damage & Repair ⓘ

DNAdam↑, 1,  

Cell Cycle & Senescence ⓘ

TumCCA↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

EMT↓, 5,   P90RSK↓, 1,   STAT3↓, 4,   TOP1↓, 3,   TumCG↓, 1,  

Migration ⓘ

E-cadherin↑, 2,   Ki-67↓, 1,   LAMs↓, 1,   MALAT1↓, 1,   MMP2↓, 3,   MMP9↓, 1,   N-cadherin↓, 2,   TumCI↓, 3,   TumCMig↓, 2,   TumMeta↓, 1,   Vim↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 2,   Hif1a↓, 3,   VEGF↓, 2,  

Barriers & Transport ⓘ

BBB↑, 1,  

Immune & Inflammatory Signaling ⓘ

NF-kB↓, 4,   NF-kB↑, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 1,   ChemoSen↑, 2,   eff↑, 1,   RadioS↑, 2,   selectivity↑, 1,  

Clinical Biomarkers ⓘ

Ki-67↓, 1,  
Total Targets: 60

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 1,   Catalase↑, 1,   GSH↑, 1,   ROS↓, 1,  

Immune & Inflammatory Signaling ⓘ

Inflam↓, 1,  

Functional Outcomes ⓘ

cognitive↑, 1,   motorD↑, 1,   neuroP↑, 1,   toxicity↓, 2,  
Total Targets: 9

Scientific Paper Hit Count for: EMT, Epithelial-Mesenchymal Transition
5 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#:96  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

Home Page