Database Query Results : Betulinic acid, , MMPs

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)

MMPs, Matrix metalloproteinases: Click to Expand ⟱

Source:

Type:

Family of zinc-dependent proteolytic enzymes that play a key role in degrading the extracellular matrix (ECM).; are metalloproteinases that are calcium-dependent zinc-containing endopeptidases;[1] other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily.[2]
MMP secretion: matrix metalloproteinase (MMP) is a kind of enzymes secreted.
by tumor cell to degrade ECM, facilitating the migration of tumor cells.

MMPs are generally considered protumorigenic due to their role in promoting tumor invasion, metastasis, and angiogenesis. They facilitate the breakdown of the extracellular matrix, allowing cancer cells to invade surrounding tissues and spread to distant sites.

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↑,

2737-

BetA,

Multiple molecular targets in breast cancer therapy by betulinic acid

Review,

Var,

TumCP↓, Betulinic acid (BA), a pipeline anticancer drug, exerts anti-proliferative effects on breast cancer cells is mainly through inhibition of cyclin and topoisomerase expression, leading to cell cycle arrest.
Cyc↓,
TOP1↓,
TumCCA↑,
angioG↓, anti-angiogenesis effect by inhibiting the expression of transcription factor nuclear factor kappa B (NF-κB), specificity protein (Sp) transcription factors, and vascular endothelial growth factor (VEGF) signaling.
NF-kB↓, Inhibition of NF-kB signaling pathway
Sp1/3/4↓,
VEGF↓,
MMPs↓, inhibiting the expression of matrix metalloproteases
ChemoSen↑, Synergistically interactions of BA with other chemotherapeutics are also described in the literature.
eff↑, BA is highly lipid soluble [74,75], and it readily passes through membranes, including plasma and mitochondrial membranes. BA acts directly on mitochondria
MMP↓, decreases mitochondrial outer membrane potential (MOMP), leading to increased outer membrane permeability, generation of reactive oxygen species (ROS),
ROS↑,
Bcl-2↓, reducing expression of anti-apoptotic proteins Bcl-2, Bcl-XL and Mcl-1
Bcl-xL↓,
Mcl-1↓,
lipid-P↑, BA inhibits the growth of breast cancer cells via lipid peroxidation resulting from the generation of ROS
RadioS↑, The cytotoxicity effect of BA on glioblastoma cells is not strong; however, some studies indicate that the combination of BA and radiotherapy could represent an advancement in treatment of glioblastoma [
eff↑, BA and thymoquinone inhibit MDR and induce cell death in MCF-7 breast cancer cells by suppressing BCRP [

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 2

Pathway results for Effect on Cancer / Diseased Cells:

Drug Metabolism & Resistance ⓘ

ChemoSen↑, 1, eff↑, 2, RadioS↑, 1,
Total Targets: 26

Pathway results for Effect on Normal Cells:

Total Targets: 0

Scientific Paper Hit Count for: MMPs, Matrix metalloproteinases

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#:204  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

Database Query Results : Betulinic acid, , MMPs

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Cell Death ⓘ

Kinase & Signal Transduction ⓘ

Transcription & Epigenetics ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Pathway results for Effect on Normal Cells:

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