Betulinic acid Cancer Research Results

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)

Betulinic acid — Betulinic acid is a naturally occurring lupane-type pentacyclic triterpenoid with broad experimental anticancer activity, especially against melanoma, neuroectodermal, glioma, breast, colorectal, and other solid-tumor models. It is a natural-product small molecule, usually abbreviated BA or BetA, and is found in several plants, classically birch bark, with semi-synthesis commonly starting from betulin. A distinguishing feature is preferential induction of tumor-cell death through direct mitochondrial injury with relative sparing of many non-neoplastic cells in preclinical systems. Its main translational limitation is very poor aqueous solubility with correspondingly weak oral/systemic developability unless formulation or derivatization is used.

Primary mechanisms (ranked):

Direct mitochondrial membrane permeabilization with intrinsic apoptosis activation
Mitochondrial ROS increase with collapse of mitochondrial membrane potential and cytochrome c release
ER-stress and unfolded-protein-response activation, including GRP78-linked stress signaling
Suppression of NF-κB and other pro-survival transcriptional programs, including Sp-family signaling in some models
Cell-cycle arrest with reduced cyclin/CDK signaling
Anti-migratory and anti-invasive effects via EMT, FAK, ROCK1, MMP, and cytoskeletal remodeling pathways
Secondary metabolic suppression of aerobic glycolysis and hypoxia-response signaling in susceptible models
Adjunct sensitization to chemo- or radiotherapy in selected preclinical settings

Bioavailability / PK relevance: Betulinic acid is highly lipophilic and poorly water-soluble, which strongly limits oral absorption and systemic exposure. PK behavior is formulation-dependent, and much of the translational literature focuses on nanoparticles, liposomes, micelles, conjugates, or topical delivery rather than conventional oral dosing.

In-vitro vs systemic exposure relevance: Many in-vitro anticancer studies use low-to-mid micromolar concentrations, which are often difficult to reproduce reliably in vivo with unformulated parent betulinic acid. Accordingly, mechanistic findings are useful biologically, but direct concentration matching to standard oral/systemic use is often poor unless enhanced-delivery systems are used.

Clinical evidence status: Strong preclinical and formulation-development literature; very limited human oncology evidence. Cancer-facing clinical development appears to remain early-phase/topical, with orphan designation for topical metastatic melanoma but no FDA approval for that indication. Betulinic acid itself is not an established approved anticancer drug.

-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↑, Casp">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

Mechanistic profile

Rank	Pathway / Axis	Cancer Cells	Normal Cells	TSF	Primary Effect	Notes / Interpretation
1	Mitochondrial permeabilization	↑ MOMP, ↓ ΔΨm, ↑ cytochrome c release, ↑ apoptosis	↔ / milder effect	P-R	Core tumor-selective death trigger	Best-supported central mechanism; helps explain activity in apoptosis-competent but therapy-resistant tumors.
2	Mitochondrial ROS increase	↑ ROS	↔ / possible antioxidant sparing (context-dependent)	P-R	Amplifies mitochondrial stress and death signaling	ROS appears mechanistically relevant in many tumor models, but not every study makes it the dominant initiating event.
3	Caspase axis and caspase-independent death	↑ caspase-9, ↑ caspase-3, ↑ PARP cleavage; caspase-independent death also reported	↔	R-G	Executes apoptosis after mitochondrial injury	BA can still kill some tumor cells when classical caspase execution is partly blocked, indicating non-canonical death contribution.
4	ER stress / UPR / GRP78	↑ ER stress, ↑ UPR, ↑ GRP78 stress signaling	↔	R-G	Links proteostatic stress to apoptosis and metastasis suppression	Especially relevant in breast and gastric cancer models; may also connect to metabolic suppression and chemosensitization.
5	NF-κB survival signaling	↓ NF-κB	↔ / ↓ inflammatory tone	R-G	Reduces survival, inflammatory, and resistance programs	Common downstream convergence node across several tumor types.
6	Cell-cycle machinery	↓ cyclin D1, ↓ CDK2, ↓ CDK4, ↑ cell-cycle arrest	↔	G	Slows proliferation	Usually supportive rather than primary; often follows stress and survival-pathway disruption.
7	EMT / invasion / matrix remodeling	↓ EMT, ↓ FAK, ↓ ROCK1, ↓ MMP2, ↓ MMP9, ↓ migration, ↓ invasion	↔	G	Antimetastatic effect	Consistent with reduced motility and invasive phenotype in multiple solid-tumor models.
8	Glycolysis	↓ glucose uptake, ↓ lactate, ↓ ECAR, ↓ HK2, ↓ PKM2, ↓ LDHA	↔	G	Secondary metabolic suppression	Not the universal initiating mechanism; appears important in selected breast-cancer and GRP78-linked systems.
9	HIF-1α hypoxia axis	↓ HIF-1α, ↓ VEGF, ↓ GLUT1, ↓ PDK1	↔	G	Reduces hypoxic adaptation and angiogenic drive	Relevant in hypoxic tumor biology and helps explain antiangiogenic/metabolic effects in some models.
10	NRF2 / antioxidant buffering	↓ NRF2 or ↓ redox buffering (model-dependent)	↔ / possible preservation of antioxidant tone (context-dependent)	R-G	May widen tumor redox vulnerability	Direction is not uniform across all models; safer to treat this as contextual rather than universally core.
11	Ca²⁺ stress	↑ Ca²⁺ (context-dependent)	↔	P-R	Supports organelle stress and apoptotic signaling	Usually part of the broader mitochondrial/ER stress network rather than a stand-alone primary target.
12	Radiosensitization or Chemosensitization	↑ sensitivity to radiation or selected drugs	Unclear	G	Adjunct leverage	Preclinical evidence supports additive or sensitizing effects with irradiation and with some chemotherapy settings, but this is not yet clinically established.
13	Clinical Translation Constraint	Poor solubility and limited systemic exposure constrain reproducibility	Same formulation constraint	G	Delivery bottleneck	Main barrier is not lack of mechanistic richness but drug-like exposure; translation currently depends heavily on formulation, derivatization, or topical/local use.

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)

Scientific Papers found: Click to Expand⟱

2755-

BetA,

Cytotoxic Potential of Betulinic Acid Fatty Esters and Their Liposomal Formulations: Targeting Breast, Colon, and Lung Cancer Cell Lines

in-vitro,

Colon,

HT29

in-vitro,

BC,

MCF-7

in-vitro,

Lung,

H460

eff↑, BA-Lip exerted stronger cytotoxic effects than the parent compound,
Casp3↑, BA’s fatty esters and their respective liposomal formulations facilitated apoptosis in cancer cells by inducing nuclear morphological changes and increasing caspase-3/-7 activity.
Casp7↑,
NF-kB↓, BA antiproliferative effects against U87MG and A172 glioblastoma cells revealing the downregulation of the NF-κB pathway and upregulation of caspase-3 and -9, thus suggesting that apoptosis occurred through mitochondria-mediated mechanisms

2763-

BetA,

Betulinic Acid Inhibits the Stemness of Gastric Cancer Cells by Regulating the GRP78-TGF-β1 Signaling Pathway and Macrophage Polarization

in-vitro,

GC,

GRP78/BiP↓, The results indicated that BA inhibited not only GRP78-mediated stemness-related protein expression and GRP78-TGF-β-mediated macrophage polarization
TGF-β↓, BA Inhibits the Expression of GRP78, TGF-β1, and Stemness Markers in Human Gastric Cancer Cells
ChemoSen↑, BA is a promising candidate for clinical application in combination-chemotherapy targeting cancer stemness.
CSCs↓,
SMAD2↓, BA inhibited TGF-β/Smad2/3 signaling, TGF-β1 secretion, and OCT4 expression in a dose-dependent manner
SMAD3↓,
OCT4↓,

2762-

BetA,

Targeting Effect of Betulinic Acid Liposome Modified by Hyaluronic Acid on Hepatoma Cells In Vitro

in-vitro,

Liver,

HepG2

ROCK1↓, BA, BA-L, and HA-BA-L downregulated the expression of ROCK1, IP3, and RAS in HepG2 cells,
RAS↓,
*BioAv↓, However, its shortcomings, namely poor water solubility and low bioavailability of BA in vivo, limit its clinical application.
BioAv↑, Liposomes can effectively improve the bioavailability of BA. Therefore, the development of liposomal BA delivery can further enhance its efficacy.

2761-

BetA,

Betulinic acid increases lifespan and stress resistance via insulin/IGF-1 signaling pathway in Caenorhabditis elegans

in-vivo,

Nor,

Insulin↓, BA improves insulin sensitivity in metabolic syndrome rats (51), but inhibits insulin/IGF-1 receptor signaling to suppress de novo lipogenesis in HepG2 cells
IGF-1↓,
*SOD↑, figure 4
*Catalase↑,
*GSH↑,
*MDA↓,
*antiOx?, Betulinic acid has robust antioxidant activity in vivo.

2760-

BetA,

A Review on Preparation of Betulinic Acid and Its Biological Activities

Review,

Var,

Review,

Stroke,

AntiTum↑, BA is considered a future promising antitumor compound
Cyt‑c↑, BA stimulated mitochondria to release cytochrome c and Smac and cause further apoptosis reactions
Smad1↑,
Sepsis↓, Administration of 10 and 30 mg/kg of BA significantly improved survival against sepsis and attenuated lung injury.
NF-kB↓, BA inhibited nuclear factor-kappa B (NF-κB) expression in the lung and decreased levels of cytokine, intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9)
ICAM-1↓,
MCP1↓,
MMP9↓,
COX2↓, In hPBMCs, BA suppressed cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PEG2) production by inhibiting extracellular regulated kinase (ERK) and Akt phosphorylation and thereby modulated the NF-κB signaling pathway
PGE2↓,
ERK↓,
p‑Akt↓,
*ROS↓, BA significantly decreased the mortality of mice against endotoxin shock and inhibited the production of PEG2 in two of the most susceptible organs, lungs and livers [80]. Moreover, BA reduced reactive oxygen species (ROS) formation
*LDH↓, and the release of lactate dehydrogenase
*hepatoP↑, hepatoprotective effect of BA from Tecomella undulata.
*SOD↑, Pretreatment of BA prevented the depletion of hepatic antioxidants superoxide dismutase (SOD) and catalase (CAT), reduced glutathione (GSH) and ascorbic acid (AA) and decreased the CCl4-induced LPO level
*Catalase↑,
*GSH↑,
*AST↓, A also attenuated the elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) plasma level,
*ALAT↓,
*RenoP↑, BA also exhibits renal-protective effects. Renal fibrosis is an end-stage renal disease symptom that develops from chronic kidney disease (CKD).
*ROS↓, BA protected against this ischemia-reperfusion injury in a mice model by enhancing blood flow and reducing oxidative stress and nitrosative stress
*α-SMA↓, Moreover, BA reduced the expression of α-smooth muscle actin (α-SMA) and collagen-I

2759-

BetA,

Chemopreventive and Chemotherapeutic Potential of Betulin and Betulinic Acid: Mechanistic Insights From In Vitro, In Vivo and Clinical Studies

Review,

Var,

chemoPv↑, chemopreventive and chemotherapeutic effects of betulin and betulinic acid by presenting in vitro, in vivo
ChemoSen↑,
*Inflam↓, right side depicts anti-inflammatory effect by suppressing proinflammatory mediators
*NRF2↑, boosting NRF2 (antioxidant/anti-inflammatory).
*NF-kB↓, suppressing proinflammatory mediators (NF-κB and COX)
*COX2↓,
ROS↑, By rapidly increasing the generation of reactive oxidative species and concurrently dissipating mitochondrial membrane potential in a dose- and time-dependent manner, betulinic acid also has an anticancer effect on melanoma cells
MMP↓,
Sp1/3/4↓, nude mice bearing LNCaP cell xenografts has been observed by betulinic acid treatment and this result was associated with reduction in the expression of Sp1, Sp3, and Sp4 proteins and vascular endothelial growth factor (VEGF)
VEGF↓,

2758-

BetA,

Betulinic Acid Attenuates Oxidative Stress in the Thymus Induced by Acute Exposure to T-2 Toxin via Regulation of the MAPK/Nrf2 Signaling Pathway

in-vivo,

Nor,

mice

*ROS↓, protective effects and mechanisms of BA in blocking oxidative stress caused by acute exposure to T-2 toxin in the thymus of mice was studied.
*MDA↓, BA pretreatment reduced ROS production, decreased the MDA content, and increased the content of IgG in serum and the levels of SOD and GSH in the thymus.
*SOD↑,
*GSH↑,
*p‑p38↓, BA downregulated the phosphorylation of the p38, JNK, and ERK proteins, while it upregulated the expression of the Nrf2 and HO-1 proteins in thymus tissues.
*p‑JNK↓,
*p‑ERK↓,
*NRF2↑,
*HO-1↑,
*MAPK↓, suppressing the MAPK signaling pathway.
*heparanase↑, BA also showed protective activities against alcohol-induced liver damage and dexamethasone-induced spleen and thymus oxidative damage, and these protective effects were related to the antioxidant capacity of BA
*antiOx↑, BA Increased T-2 Toxin-Induced Thymus Antioxidative Capacity

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↑,

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↓,

2764-

BetA,

In silico profiling of histone deacetylase inhibitory activity of compounds isolated from Cajanus cajan

Analysis,

Var,

HDAC↓, betulinic acid might be a suitable HDAC inhibitor worthy of further investigation in order to be used for regulating conditions associated with overexpression of HDACs.

2754-

BetA,

Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors

in-vitro,

Pca,

LNCaP

VEGF↓, betulinic acid decreases expression of vascular endothelial growth (VEGF)
survivin↓, and the antiapoptotic protein survivin
Sp1/3/4↓, betulinic acid acts as a novel anticancer agent through targeted degradation of Sp proteins that are highly overexpressed in tumors.
Casp↑, Betulinic acid also induced caspase-dependent PARP cleavage in LNCaP cells, and this was accompanied by decreased expression of the antiapoptotic protein survivin
PARP↑,
survivin↓,
angioG↓, betulinic acid also induces proapoptotic and antiangiogenic responses in LNCaP cells as evidenced by decreased expression of VEGF and survivin and activation of caspase-dependent PARP cleavage

2753-

BetA,

Betulinic acid induces apoptosis by regulating PI3K/Akt signaling and mitochondrial pathways in human cervical cancer cells

in-vitro,

Cerv,

HeLa

30 µmol/l BA

PI3K↓, BA treatment acted through downregulating a phosphatidylinositol 3-kinase (PI3K) subunit and suppressing the Akt phosphorylation at Thr308 and Ser473 after increasing the generation of intracellular reactive oxygen species
p‑Akt↓,
ROS↑,
TumCCA↑, BA induced cell cycle arrest at the G0/G1 phase, which was consistent with the cell cycle-related protein results in which BA significantly enhanced the expression of p27Kip and p21Waf1/Cip1 in HeLa cells.
p27↑,
P21↑,
mt-Apoptosis↑, mitochondrial apoptosis, as reflected by the increased expression of Bad and caspase-9
BAD↑,
Casp9↑,
MMP↓, decline in mitochondrial membrane potential.
eff↓, preincubation of the cells with glutathione (antioxidant) blocked the process of apoptosis, prevented the phosphorylation of downstream substrates.

2752-

BetA,

Betulinic acid: a natural product with anticancer activity

Review,

Var,

selectivity↑, nontransformed cells of different origin, e.g., fibroblasts, melanocytes, neuronal cells and peripheral blood lymphocytes, have been reported to be much more resistant to the cytotoxic effect of BA than cancer cells
ChemoSen↑, BA was found to cooperate with various chemotherapeutic drugs, including doxorubicin, etoposide, cisplatin, taxol, and actinomycin D, to induce apoptosis and to inhibit clonogenic survival of tumor cells
RadioS↑, These reports suggest that using BetA as sensitizer in chemotherapy-, radiotherapy-, or TRAIL-based combination regimens may be a novel strategy to enhance the efficacy of anticancer therapy.
MMP↓, BA directly induces loss of mitochondrial membrane potenti
cl‑Casp3↑, BA, induced cleavage of both caspases-8 and -3 in cytosolic extracts.
Cyt‑c↑, cytochrome c, released from mitochondria undergoing BA-mediated permeability transition, activated caspase-3 but not caspase-8 in a cell-free system.
ROS↑, Cleavage of caspases-3 and -8 was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species (ROS).
NF-kB↑, BA is a potent activator of NF-kB in a variety of tumor cell lines.
TOP1↓, BA blocks the catalytic activity of topoisomerase I by abrogating the inter- action of the enzyme and the DNA substrate

2751-

BetA,

Betulinic acid inhibits proliferation and triggers apoptosis in human breast cancer cells by modulating ER (α/β) and p53

in-vitro,

BC,

MDA-MB-231

in-vitro,

BC,

MCF-7

tumCV↓, After BA treatment, the cell viability of MCF-7 and MDA-MB-231 significantly reduced as early as the minimal concentration of 2.5 μM BA at both 24 and 48 h
ER-α36↓, Upon treating the cells with BA, the expression levels of ERα in MCF-7 and MDA-MB-231 significantly decreased in all BA concentrations, particularly in the highest one of 30 μM

2750-

BetA,

GEM,

Betulinic acid, a major therapeutic triterpene of Celastrus orbiculatus Thunb., acts as a chemosensitizer of gemcitabine by promoting Chk1 degradation

in-vitro,

PC,

Bxpc-3

in-vitro,

Lung,

H1299

CHK1↓, Betulinic acid destabilized Chk1 protein and conferred chemopotentiating effects of gemcitabine in vitro and in vivo
ChemoSen↑,
tumCV↓, A combination therapy of gemcitabine with betulinic acid produced synergistic pharmacologic interaction on cell viability, apoptosis and DNA double-strand breaks.
Apoptosis↑,
DNAdam↑,

2749-

BetA,

Anti-Inflammatory Activities of Betulinic Acid: A Review

Review,

Nor,

Inflam↓, betulinic acid as a promissory lead compound with anti-inflammatory activity
*NO↓, BA can inhibit the production of NO, mainly in macrophages cultures stimulated with bacterial lipopolysaccharide (LPS) and/or interferon gamma (IFN-ɣ)
*IL10↑, (BA) has a broad-spectrum anti-inflammatory activity, significantly increasing IL-10 production, decreasing ICAM-1, VCAM-1, and E-selectin expression and inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB),
*ICAM-1↓,
*VCAM-1↓,
*E-sel↓,
*NF-kB↓,
*IKKα↓, BA blocks the NF-κB signaling pathway by inhibiting IκB phosphorylation and d
*COX2↓, BA also inhibits cyclooxygenase-2 (COX-2) activity and, therefore, decrease prostaglandin E2 (PGE2) synthesis
*PGE2↓,
*IL1β↓, The production of critical pro-inflammatory cytokines, such as IL-1β, IL-6, IL-8, IL-12, and TNF, is also decreased by BA treatment
*IL6↓,
*IL8↓,
*IL12↓,
*TNF-α↑,
*HO-1↑, induction of HO-1 enzyme activity is associated with the anti-inflammatory effect of BA, since SnPP, an inhibitor of HO-1, promoted a partial reversal of BA’s effect on NF-κB activity,
*IL10↑, BA also increased the amount of IL-10, a well-known anti-inflammatory cytokine
*IL2↓, decreasing the production of pro-inflammatory cytokines, such as IL-2, IL-6, IL-17, and IFN-γ
*IL17↓,
*IFN-γ↓,
*SOD↑, BA decreased the production of the inflammatory mediators described above at the inflammation site and increased enzyme activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GRd) in the liver
*GPx↑,
*GSR↑,
*MDA↓, BA decreased malondialdehyde (MDA) levels, a key mediator of oxidative stress and widely used as a marker of free radical mediated lipid peroxidation injury, at the inflammation site
*MAPK↓, BA downregulates MAPK signaling pathways (ERK1/2, JNK, and p38) in the paw edema tissue, which, in part, explains the inhibition of cytokine production (IL-1β and TNF), COX-2 expression, and PGE2 production (Figure 3).

2748-

BetA,

Betulinic Acid: Recent Advances in Chemical Modifications, Effective Delivery, and Molecular Mechanisms of a Promising Anticancer Therapy

Review,

Var,

Bcl-2↓, Cell death stimuli activate prodeath BCL-2 family proteins that in turn permeabilize mitochondrial outer membrane, thereby resulting in the release of Cyt C
MMP↓,
Cyt‑c↑,
Casp↑, Smac (second mitochondria-derived activator of caspase)/DIABLO (direct inhibitor of apoptosis [IAP] binding protein with low pI), and AIF (apoptosis-inducing factor) into the cytoplasm (27
Diablo↑,
AIF↑,
angioG↓, BetA's inhibition of growth-factor-induced angiogenesis seems at least partially owing to modulation of mitochondrial function in endothelial cells
BioAv↓, Current methods of conventional drug delivery using oral liquids or tablets are generally inefficient, with poor biodis- tribution, low solubility, long-term toxicity, and limited drug efficacy due to partial biodegradation, swelling, and ero- sion
NF-kB↓, BetA treatment inhibits the activation of NF-kB

2747-

BetA,

Betulinic acid, a natural compound with potent anticancer effects

Review,

Var,

selectivity↑, potently effective against a wide variety of cancer cells, also those derived from therapy-resistant and refractory tumors, whereas it has been found to be relatively nontoxic for healthy cells
Cyt‑c↑, induces Bax/Bak-independent cytochrome-c release.
*toxicity↓, In general, BetA is concluded to be less toxic to cells from healthy tissues.
TOP1↓, topoisomerase I/II
NF-kB↓, transcription factor NF-kB
ROS↑, Consistently, in glioma cells BetA-induced ROS generation
RadioS↑, Treatment with BetA in combination with irradiation resulted in additive growth inhibition of melanoma cells.
ChemoSen↑, BetA cooperated with anticancer drugs, doxorubicin and etoposide, to induce apoptosis and to inhibit clonogenic survival in SHEP neuroblastoma cells

5585-

BetA,

Betulinic acid-induced mitochondria-dependent cell death is counterbalanced by an autophagic salvage response

in-vitro,

Cerv,

HeLa

in-vitro,

lymphoma,

U937

mtDam↑, It was shown to induce apoptosis via a direct effect on mitochondria.
TumAuto↑, autophagy is activated as a response to the mitochondrial damage inflicted by BetA

5593-

BetA,

Betulinic acid decreases specificity protein 1 (Sp1) level via increasing the sumoylation of sp1 to inhibit lung cancer growth

in-vitro,

Lung,

Sp1/3/4↓, Betulinic acid decreases specificity protein 1 (Sp1) level
cycA1/CCNA1↓, The down-regulation of cyclin A2 by BA treatment resulted in decreased retinoblastoma protein phosphorylation and cell cycle G(2)/M arrest.
p‑RB1↓,
TumCCA↑,

5592-

BetA,

Betulin induces mitochondrial cytochrome c release associated apoptosis in human cancer cells

in-vitro,

Liver,

HepG2

10 to 15 mg/mL

in-vitro,

Cerv,

HeLa

Casp3↑, The sequential activation of caspase-9 and caspase-3/-7 and the cleavage of poly(ADP-ribose) polymerase (PARP) were observed behind those mitochondrial events.
Casp9↑,
cl‑PARP↑,
Apoptosis↑, betulin triggers apoptosis of human cancer cells through the intrinsic apoptotic pathway.
Cyt‑c↑, associated with mito- chondrial cytochrome c and Smac release and depolarization of the mitochondrial membrane potential.
MMP↓,

5591-

BetA,

Advances and challenges in betulinic acid therapeutics and delivery systems for breast cancer prevention and treatment

Review,

BC,

IC50 values ranging from 1 to 13.0 μg mL−1

BioAv↓, However, its poor water solubility limits its optimal therapeutic potential.
BioAv↑, nano-drug delivery systems (NDDSs) have gained significant attention as a method to substantially improve low solubility and poor drug bioavailability, enhance targeted drug delivery, and reduce side effects.
selectivity↑, reviews by Simone Fulda23,24 strengthened BA's potential for cancer treatment and prevention, particularly its ability to selectively trigger apoptosis in cancer cells while causing minimal harm to normal cells.
eff↑, It is important to note that the anticancer effects of BA on different types of tumors are more potent at a pH lower than 6.8.34
angioG↓, figure 3
*antiOx↑,
*Inflam↓,
MMP↓, BA-induced mitochondrial depolarization
Bcl-2↓, BA treatment has been shown to lower Bcl-2 expression and increase Bax, resulting in the activation of caspase-9 and caspase-3 through the mitochondrial pathway.63
BAX↑,
Casp9↑,
Casp3↑,
GRP78/BiP?, BA directly targets GRP78, triggering ER stress by activating the PERK-eIF2α-CHOP apoptotic cascade
ER Stress↑,
PERK↑,
CHOP↑,
ChemoSen↑, BA's ability to chemosensitize BC cells to taxanes highlights its importance in situations of drug resistance
SESN2↑, Under hypoxia, BA strongly increases SESN2 expression.
ROS↑, Reducing SESN2 levels enhances BA-induced ROS production, DNA damage, and radiosensitivity, while decreasing autophagic flux, indicating that SESN2-mediated autophagy serves as a protective adaptive response.68
MOMP↓, decreases the mitochondrial outer membrane potential (MOMP),
MAPK↑, This leads to the activation of p38 Mitogen-activated protein kinase (p38 MAPK), the release of cytochrome C, apoptosis-inducing factor (AIF),
Cyt‑c↑,
AIF↑,
STAT3↓, BA suppresses the signal transducer and activator of transcription (STAT) 3 signaling pathways
FAK↓, BA's inhibition of STAT3, as well as FAK, leads to decreased expression of MMPs and elevated TIMP-2, thereby impairing cancer cell migration and invasion
TIMP2↑,
TumCMig↓,
TumCI↓,
Sp1/3/4↓, Sp inhibition reduces cancer gene expression, inhibiting cancer cell growth.
TumCCA↑, It increases cell numbers in the G2/M phase, leading to cell cycle arrest.
DNAdam↑, causes DNA damage, thereby inhibiting the progression and invasion of cancer cells.

5590-

BetA,

Betulinic acid a radiosensitizer in head and neck squamous cell carcinoma cell lines

in-vitro,

HNSCC,

SCC9

in-vitro,

HNSCC,

SCC25

RadioS↑, betulinic acid alone inhibits cell survival, affects cell survival additively in combination with irradiation and decreases clonogenic survival in both cell lines when applied alone.

5589-

BetA,

Advancements in Betulinic Acid-Loaded Nanoformulations for Enhanced Anti-Tumor Therapy

Review,

Var,

BioAv↓, BA is greatly hindered by its poor water solubility, low bioavailability, and off-target toxicity
toxicity↝,
BioAv↑, nanoparticles, liposomes, micelles, and nanofibers, aiming to improve its solubility and bioavailability, prolong plasma half-life, and enhance targeting ability, thereby augmenting its anti-cancer efficacy
Half-Life↑,

5588-

BetA,

Therapeutic applications of betulinic acid nanoformulations

Review,

Var,

BioAv↓, Despite the pharmacological activity of BA, it has been associated with some drawbacks, such as poor aqueous solubility and short half-life in vivo, which limit therapeutic application.
Half-Life↓,
BioAv↑, enhancing BA's aqueous solubility, half-life, and efficacy by using nanoscale drug delivery systems.
Half-Life↑,

5587-

BetA,

Rad,

Effects of betulinic acid alone and in combination with irradiation in human melanoma cells

in-vitro,

Melanoma,

TumCG↓, Betulinic acid strongly and consistently suppressed the growth and colony-forming ability of all human melanoma cell lines investigated.
RadioS↑, In combination with ionizing radiation the effect of betulinic acid on growth inhibition was additive in colony-forming assays.
Apoptosis↑, Betulinic acid also induced apoptosis in human melanoma cells as demonstrated by Annexin V binding and by the emergence of cells with apoptotic morphology
selectivity↑, growth-inhibitory action of betulinic acid was more pronounced in human melanoma cell lines than in normal human melanocytes.

5586-

BetA,

Suppression of HIF-1α accumulation by betulinic acid through proteasome activation in hypoxic cervical cancer

in-vitro,

Cerv,

HeLa

Hif1a↓, We found that BA inhibited the hypoxia-induced accumulation of HIF-1α without affecting HIF-1α mRNA levels
VEGF↓, suppressed the expression of HIF target genes, including VEGF, GLUT1, and PDK1 in HeLa cells.
GLUT1↓,
PDK1↓,

2746-

BetA,

Betulinic acid induces apoptosis and inhibits metastasis of human colorectal cancer cells in vitro and in vivo

in-vitro,

CRC,

HCT116

in-vivo,

CRC,

20 mg/kg/day of BA

TumCG↓, BA inhibited colorectal cancer cell lines in vitro with a time-dependent and dose-dependent manner.
BAX↑, upregulating expression of Bax and cleaved caspase-3 and downregulating protein of Bcl-2
Bcl-2↓,
ROS↑, BA could increase the production of reactive oxygen species and reduce mitochondrial membrane potential of cancer cell, suggesting that BA induced cancer cells apoptosis by mitochondrial mediated pathways
MMP↓,
TIMP2↑, BA significantly inhibited the migration and invasion of colorectal cancer cells, reduced the expression of matrix metalloproteinase (MMPs) and increased the expression of MMPs inhibitor (TIMP-2).
TumVol↓,

5584-

BetA,

Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumors

in-vitro,

GBM,

A172

in-vitro,

GBM,

U118MG

in-vitro,

GBM,

U251

Apoptosis↑, BetA induced apoptosis by a direct effect on mitochondria independent of accumulation of wild-type p53 protein and independent of death-inducing ligand/receptor systems such as CD95.
P53↑,
Cyt‑c↑, release of soluble apoptogenic factors such as cytochrome c or AIF from mitochondria into the cytosol, where they induced activation of caspases.
AIF↑,
Casp↑,
AntiTum↑, BetA exhibited potent antitumor activity on neuroblastoma cells resistant to CD95- or doxorubicin-triggered apoptosis and on primary tumor cells from patients with neuroectodermal tumors.
MMP↓, BetA resulted in loss of the mitochondrial membrane potential

5583-

BetA,

Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells

vitro+vivo,

NA,

ROS↑, Formation of reactive oxygen species [6], modulation of BCL-2 and BAX levels [8] and topoisomerases Ia and IIa [11] have been suggested to be involved in its mechanisms of action.
Bcl-2↓,
BAX↑,
TOP1↝,
eff↝, betulinic acid was more than ten times less potent than doxorubicin
toxicity↓, Thus on normal PBL betulinic acid was at least 1000-fold less toxic than doxorubicin.
toxicity↓, Mice treated with betulinic acid did not show any sign of apparent toxicity or body weight loss compared with controls.
selectivity↑, Moreover, in spite of the lower potency compared with doxorubicin, betulinic acid seems to be selective for tumor cells, since minimal toxicity against normal cells was observed

5582-

BetA,

Targeting mitochondrial apoptosis by betulinic acid in human cancers

Review,

Var,

Apoptosis↑, BA has been reported to induce apoptosis via a direct effect on mitochondria.
MMP↓, BA triggered loss of mitochondrial membrane potential
Cyt‑c↑, BA was shown to trigger cytochrome c in a permeability transition pore-dependent
ROS↑, Generation of ROS upon treatment with BA has been reported to be involved in initiating mitochondrial membrane permeabilization [15].
NF-kB↑, These findings indicate that the activation of NF-kB by BA promotes BA-induced apoptosis in a cell type- specific manner.
angioG↓, antiangiogenic activity of BA was linked to its mitochondrial damaging effects [33]
mtDam↑,
TOP1↓, BA can inhibit the catalytic activity of topoisomerase I
selectivity↑, normal cells of different origin have been reported to be much more resistant to BA than cancer cells pointing to some tumor selectivity [19,25,44,45].
ChemoSen↑, his suggests that BA can be used as a sensitizer in combination regimens to enhance the efficacy of anticancer therapy or to bypass some forms of drug resistance
TumCG↓, BA also suppressed tumor growth in several animal models of human cancer.
chemoPv↑, BA has also been reported to act as a chemopreventive agent.
RadioS↑, BA may also be used in combination protocols to enhance its antitumor activity, for example with chemo- or radiotherapy or with the death receptor ligand TRAIL. B

4273-

BetA,

Betulinic acid, a natural PDE inhibitor restores hippocampal cAMP/cGMP and BDNF, improve cerebral blood flow and recover memory deficits in permanent BCCAO induced vascular dementia in rats

in-vivo,

NA,

 (BCCAO) induced VaDin experimental rats

*neuroP↑, BA demonstrated a neuroprotective effect in a dose-dependent manner.
*BDNF↑, BA was able to re-establish cerebral blood flow, restore behavioral parameters and showed significant improvements in the as cAMP,cGMP and BDNF levels, restrain the oxidative stress and inflammatory parameters
*ROS↓,
*Inflam↓,
*cognitive↑, its ability to restore cognitive impairment and hippocampal neurochemistry in VaD.

2771-

BetA,

Cardioprotective Effect of Betulinic Acid on Myocardial Ischemia Reperfusion Injury in Rats

in-vivo,

Nor,

Rats

in-vivo,

Stroke,

*cardioP↑, Pretreatment with BA improved cardiac function and attenuated LDH and CK activities compared with IR group
*LDH↓,
eff↑, prevent cardiomyocytes apoptosis, and eventually alleviate the extent of the myocardial ischemia/reperfusion injury.

2766-

BetA,

Role of natural secondary metabolites as HIF-1 inhibitors in cancer therapy

Review,

Var,

Hif1a↓, Furthermore, it was demonstrated that betulinic acid reduces HIF-1 accumulation, which in consequence leads to a decrease in HIF-1 sensitive genes including VEGF and GLUT1 in hypoxic cervical cancer cells
VEGF↓,
GLUT1↓,

2765-

BetA,

Unveiling Betulinic Acid as a Potent CDK4 Inhibitor for Cancer Therapeutics

in-vitro,

Lung,

A549

CDK4↓, in silico and in vitro methodology, reveals Betulinic Acid’s inhibitory efficacy against CDK4 for cancer therapy

2720-

BetA,

Betulinic acid induces apoptosis of HeLa cells via ROS-dependent ER stress and autophagy in vitro and in vivo

in-vitro,

Cerv,

HeLa

Keap1↝, The findings revealed that BA activated Keap1/Nrf2 pathway and triggered mitochondria-dependent apoptosis due to ROS production.
ROS↑,
Ca+2↑, Furthermore, BA increased the intracellular Ca2+ levels
Beclin-1↓, inhibited the expression of Beclin1 and promoted the expression of GRP78, LC3-II, and p62 associated with ERS and autophagy.
GRP78/BiP↑,
LC3II↑,
p62↑,
ERStress↑,
TumAuto↑,

2728-

BetA,

Betulinic acid as new activator of NF-kappaB: molecular mechanisms and implications for cancer therapy

in-vitro,

Var,

NF-kB↑, BetA activates NF-kappaB in a variety of tumor cell lines.
IKKα↑, BetA-induced NF-kappaB activation involved increased IKK activity
eff↓, NF-kappaB inhibitors in combination with BetA would have no therapeutic benefit or could even be contraproductive in certain tumors, which has important implications for the design of BetA-based combination protocols.

2727-

BetA,

Betulinic acid in the treatment of breast cancer: Application and mechanism progress

Review,

BC,

mt-ROS↑, Its mechanisms mainly include inducing mitochondrial oxidative stress, regulating specific protein (Sp) transcription factors, inhibiting breast cancer metastasis, inhibiting glucose metabolism and NF-κB pathway.
Sp1/3/4↓, By triggering the degradation of Sp1, Sp3, and Sp4, betulinic acid reduces the transcriptional activity of these factors
TumMeta↓,
GlucoseCon↓,
NF-kB↓,
ChemoSen↑, BA can also increase the sensitivity of breast cancer cells to other chemotherapy drugs such as paclitaxel and reduce its toxic side effects.
chemoP↑,
m-Apoptosis↑, variety of mechanisms, including inducing mitochondrial apoptosis, inhibiting topoisomerase
TOP1↓, betulinic acid may inhibit the ability of topoisomerase I or II to properly cleave and re-ligate DNA strands.

2726-

BetA,

Betulinic acid induces DNA damage and apoptosis in SiHa cells

in-vitro,

Cerv,

SiHa

39.83 μg/ml

tumCV↓, BA was shown to destroy SiHa cells preferentially in a concentration dependent manner with a 50% inhibition of the cells at 39.83 μg/ml.
DNAdam↑, BA was coupled with DNA strand breaks, morphological changes, disruption of MMP, reactive oxygen species (ROS) generation and the cell arrest at G0/G1 stage of cell cycle.
MMP↓,
ROS↑,
TumCCA↑,
TOP1↓, It has been previously reported that inhibition of topoisomerases might be an additional mechanism of BA-induced cell death

2725-

BetA,

Betulinic acid protects against renal damage by attenuation of oxidative stress and inflammation via Nrf2 signaling pathway in T-2 toxin-induced mice

in-vivo,

Nor,

*RenoP↑, BA pretreatment alleviated excessive glomerular hemorrhage and inflammatory cell infiltration in kidneys caused by T-2 toxin.
*SOD?, Moreover, pretreatment with BA mitigated T-2 toxin-induced renal oxidative damage by up-regulating the activities of SOD and CAT, and the content of GSH, while down-regulating the accumulation of ROS and MDA
*Catalase↑,
*GSH↑,
*ROS↓,
*MDA↓,
*IL1β↓, decreasing the mRNA expression of IL-1β, TNF-α and IL-10, and increasing IL-6 mRNA expression
*TNF-α↓,
*IL10↓,
*IL6↑,
*NRF2↑, pretreatment with BA could activate Nrf2 signaling pathway.

2724-

BetA,

Down-regulation of NOX4 by betulinic acid protects against cerebral ischemia-reperfusion in mice

in-vivo,

Nor,

mice

in-vivo,

Stroke,

AntiTum↑, Betulinic acid is mainly known for its anti-tumor and anti-inflammatory activities.
*Inflam↓,
*ROS↓, Our previous study showed that betulinic acid could decrease the reactive oxygen species (ROS) production by regulating the expression of NADPH oxidase.
*NOX4↓, Pre-treatment with betulinic acid (50 mg/kg/day for 7 days via gavage) prior to MCA occlusion prevented the ischemia/reperfusion-induced up-regulation of NOX4 and ROS production.
*Apoptosis↓, treatment with betulinic acid could markedly blunt the ischemia/reperfusion-induced neuronal apoptosis
neuroP↑, betulinic acid protects against cerebral ischemia/reperfusion injury in mice

2723-

BetA,

Betulinic acid and oleanolic acid modulate CD81 expression and induce apoptosis in triple-negative breast cancer cells through ROS generation

in-vitro,

BC,

MDA-MB-231

Apoptosis↑, Triterpenoids such as betulinic acid (BA) and oleanolic acid (OA) have anticancer effects by inducing apoptosis in TNBC cells.
tumCV↓, The result showed that BA and OA inhibited viability of MDA-MB-231 cells.
ROS↑, BA and OA also increased intracellular ROS levels and induced apoptosis.

2722-

BetA,

Betulinic Acid for Cancer Treatment and Prevention

Review,

Var,

MMP↓, betulinic acid induced loss of mitochondrial membrane potential
Cyt‑c↑, betulinic acid was shown to trigger cytochrome c
cl‑Casp3↑, Cleavage of caspase-3 and -8 was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species.
cl‑Casp8↑,
ROS↑,
NF-kB↑, Betulinic acid was identified as a potent activator of NF-κB in a number of cancer cell lines
TOP1↓, betulinic acid was shown to inhibit the catalytic activity of topoisomerase I

2721-

BetA,

Proteomic Investigation into Betulinic Acid-Induced Apoptosis of Human Cervical Cancer HeLa Cells

in-vitro,

Cerv,

HeLa

15 µmol/L, 30 µmol/L, 50 µmol/L) of BA for 24 h, 48 h, and 72 h.

30.42±2.39 µM

ROS↑, Consistent with our results at the protein level, an increase in intracellular reactive oxygen species was observed in betulinic acid-treated cells
Dose↝, The level of ROS in BA-treated cells was 9.28-fold and 12.77-fold higher than the level of ROS in control cells for treatments of 15 µmol/L and 30 µmol/L, respectively,
Bcl-2↓, The expression level of Bcl-2 was observed to be significantly lower than the control level. In contrast, the expression of proapoptotic Bax was significantly increased compared to the controls by qRT-PCR
BAX↑,
ER Stress↑, In the present work, up-regulated protein expression was detected, which may mediate the ER process of BA in HeLa cells.

2729-

BetA,

Betulinic acid in the treatment of tumour diseases: Application and research progress

Review,

Var,

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

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↓,

2718-

BetA,

The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis

in-vitro,

AML,

U937

TumCCA↑, BA exerted a significant cytotoxic effect on U937 cells through blocking cell cycle arrest at the G2/M phase and inducing apoptosis, and that the intracellular reactive oxygen species (ROS) levels increased after treatment with BA.
Apoptosis↑,
i-ROS↑,
cycA1/CCNA1↓, down-regulation of cyclin A and cyclin B1, and up-regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 revealed the G2/M phase arrest mechanism of BA.
CycB/CCNB1↓,
P21↑,
Cyt‑c↑, BA induced the cytosolic release of cytochrome c by reducing the mitochondrial membrane potential with an increasing Bax/Bcl-2 expression ratio.
MMP↓,
Bax:Bcl2↑,
Casp9↑, BA also increased the activity of caspase-9 and -3, and subsequent degradation of the poly (ADP-ribose) polymerase.
Casp3↑,
PARP↓,
eff↓, However, quenching of ROS by N-acetyl-cysteine, an ROS scavenger, markedly abolished BA-induced G2/M arrest and apoptosis, indicating that the generation of ROS plays a key role in inhibiting the proliferation of U937 cells by BA treatment.
*antiOx↑, Accumulated evidence demonstrates that BA possesses various biological activities, including antioxidant, anti-inflammatory, hepatoprotective, and anti-tumor effects
*Inflam↓,
*hepatoP↑,
selectivity↑, BA are complex and depends on the type of cancer cells, without causing toxicity toward normal cells
NF-kB↓, Shen et al. (2019) recently reported that the suppression of the nuclear factor-kappa B pathway increased downstream oxidant effectors, thereby promoting the generation of reactive oxygen species (ROS) in BA-stimulated multiple myeloma cells.
*ROS↓, Although BA is known to have antioxidant activity that blocks the accumulation of ROS due to oxidative stress in normal cells (Cheng et al. 2019;

2717-

BetA,

Betulinic Acid Induces ROS-Dependent Apoptosis and S-Phase Arrest by Inhibiting the NF-κB Pathway in Human Multiple Myeloma

in-vitro,

Melanoma,

U266

10-40uM

in-vivo,

Melanoma,

Nude Mouse Xenograft Model

in-vitro,

Melanoma,

RPMI-8226

Apoptosis↑, BA mediated cytotoxicity in MM cells through apoptosis, S-phase arrest, mitochondrial membrane potential (MMP) collapse, and overwhelming reactive oxygen species (ROS) accumulation.
TumCCA↑, S-Phase Arrest in U266 Cells
MMP↓,
ROS↑, exhibited concentration-dependent increases in intracellular ROS
eff↓, ROS scavenger N-acetyl cysteine (NAC) effectively abated elevated ROS, the BA-induced apoptosis was partially reversed
NF-kB↓, BA resulted in marked inhibition of the aberrantly activated NF-κB pathway in MM
Cyt‑c↑, BA mediated the release of cyt c and activated cleaved caspase-3, caspase-8, and caspase-9 and cleaved PARP1
Casp3↑,
Casp8↑,
Casp9↑,
cl‑PARP1↑,
MDA↑, here is a concentration-dependent increase in MDA contents and reduction in SOD activities, especially for the high concentration group.
SOD↓,
SOD2↓, expression of genes SOD2, FHC, GCLM, and GSTM was all decreased following treatment with BA (40 μM)
GCLM↓,
GSTA1↓,
FTH1↓, FHC
GSTs↓, GSTM
TumVol↓, BA Inhibits the Growth of MM Xenograft Tumors In Vivo. BA-treated group were significantly reduced (inhibition ratio of approximately 72.1%).

2716-

BetA,

Cellular and molecular mechanisms underlying the potential of betulinic acid in cancer prevention and treatment

Review,

Var,

AntiCan↑, BA has a range of well-documented pharmacological and biological effects, including antibacterial, immunomodulatory, diuretic, antiviral, antiparasitic, antidiabetic, and anticancer activities
TumCD↑, anticancer properties of BA are mediated by the activation of cell death and cell cycle arrest, production of reactive oxygen species, increased mitochondrial permeability, modulation of nuclear factor-κB and Bcl-2 family signaling
TumCCA↑,
ROS↑,
NF-kB↓,
Bcl-2↓,
Half-Life↝, The half-life eliminations were 11.8 and 11.5 h after 500 and 250 mg/kg of intraperitoneal (i.p.) BA administration
GLUT1↓, the expression of HIF target genes, such as GLUT1, VEGF, and PDK1 was also suppressed by BA
VEGF↓,
PDK1↓,

1305-

BetA,

Betulinic acid decreases expression of bcl-2 and cyclin D1, inhibits proliferation, migration and induces apoptosis in cancer cells

in-vitro,

UEC,

Apoptosis↑,
Bcl-2↓,
BAX↑,

Showing Research Papers: 1 to 50 of 69
Page 1 of 2 Casp&page=2&exSp=open">Next

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 69

Pathway results for Effect on Cancer / Diseased Cells:

Infection & Microbiome ⓘ

Sepsis↓, 1,
Total Targets: 149

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

antiOx?, 1, antiOx↑, 3, Catalase↑, 3, GPx↑, 1, GSH↑, 4, GSR↑, 1, HO-1↑, 2, MDA↓, 4, NOX4↓, 1, NRF2↑, 3, ROS↓, 7, SOD?, 1, SOD↑, 4,

Core Metabolism/Glycolysis ⓘ

ALAT↓, 1, LDH↓, 2,

Cell Death ⓘ

Apoptosis↓, 1, p‑JNK↓, 1, MAPK↓, 2, p‑p38↓, 1,

Proliferation, Differentiation & Cell State ⓘ

p‑ERK↓, 1,

Migration ⓘ

E-sel↓, 1, heparanase↑, 1, VCAM-1↓, 1, α-SMA↓, 1,

Angiogenesis & Vasculature ⓘ

NO↓, 1,

Immune & Inflammatory Signaling ⓘ

COX2↓, 2, ICAM-1↓, 1, IFN-γ↓, 1, IKKα↓, 1, IL10↓, 1, IL10↑, 2, IL12↓, 1, IL17↓, 1, IL1β↓, 2, IL2↓, 1, IL6↓, 1, IL6↑, 1, IL8↓, 1, Inflam↓, 5, NF-kB↓, 2, PGE2↓, 1, TNF-α↓, 1, TNF-α↑, 1,

Synaptic & Neurotransmission ⓘ

BDNF↑, 1,

Drug Metabolism & Resistance ⓘ

BioAv↓, 1,

Clinical Biomarkers ⓘ

ALAT↓, 1, AST↓, 1, IL6↓, 1, IL6↑, 1, LDH↓, 2,

Functional Outcomes ⓘ

cardioP↑, 1, cognitive↑, 1, hepatoP↑, 2, neuroP↑, 1, RenoP↑, 2, toxicity↓, 3,
Total Targets: 56

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

Betulinic acid Cancer Research Results

Mechanistic profile

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 ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Infection & Microbiome ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Immune & Inflammatory Signaling ⓘ

Synaptic & Neurotransmission ⓘ

Drug Metabolism & Resistance ⓘ

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