condition found tbRes List
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
-half-life reports vary 3-5 hrs?.
BioAv -hydrophobic molecule with relatively poor water solubility.

Pathways:
- 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: NRF2↓, SOD↓, GSH↓
- Raises AntiOxidant defense in Normal Cells: NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- 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↓, Sp proteins↓,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, CDK2↓, CDK4↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, FAK↓, ERK↓, EMT↓, TOP1↓,
- inhibits glycolysis ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, HK2↓, ECAR↓, GRP78↑, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓,
- inhibits Cancer Stem Cells : CSC↓, GLi1↓, β-catenin↓, OCT4↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, β-catenin↓, AMPK↓, ERK↓, JNK,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,
- Selectivity: Cancer Cells vs Normal Cells


TumCCA, Tumor cell cycle arrest: Click to Expand ⟱
Source:
Type:
Tumor cell cycle arrest refers to the process by which cancer cells stop progressing through the cell cycle, which is the series of phases that a cell goes through to divide and replicate. This arrest can occur at various checkpoints in the cell cycle, including the G1, S, G2, and M phases. S, G1, G2, and M are the four phases of mitosis.
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

2744- BetA,    Betulin and betulinic acid: triterpenoids derivatives with a powerful biological potential
- Review, Var, NA
Apoptosis↓, Various studies have demonstrated that BE is able to induce apoptosis in numerous cancer cell lines (
TumCCA↑, 10 uM concentration, BE arrests cell cycle of murine melanoma B164A5 cells in S phase.
Casp9↑, BE is involved in the sequential activation of caspase-9, caspases 3 and 7, and cleaving of poly(ADP-ribose) polymerase (PARP) (Potze et al. 2014).
Casp3↑,
Casp7↑,
cl‑PARP↑,
MMP↓, mitochondrial membrane potential loss (Li et al. 2010; Potze et al. 2014).
ROS↑, increased reactive oxygen species (ROS) production
TOP1↓, BA was also shown to inhibit the proliferation of topoisomerases and therefore express anti-proliferative activity
NF-kB↓, BA was demonstrated to inhibit activating of NF-kB

2753- BetA,    Betulinic acid induces apoptosis by regulating PI3K/Akt signaling and mitochondrial pathways in human cervical cancer cells
- in-vitro, Cerv, HeLa
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.

2716- BetA,    Cellular and molecular mechanisms underlying the potential of betulinic acid in cancer prevention and treatment
- Review, Var, NA
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↓,

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 - in-vivo, Melanoma, NA - 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%).

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↓, 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↓,
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;

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 - in-vitro, Bladder, UMUC3 - in-vitro, Bladder, 5637
TumCD↑, BA induced cell death in bladder cancer cells and that are accompanied by apoptosis, necrosis, and cell cycle arrest.
Apoptosis↑,
TumCCA↑,
CycB↓, 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↓,
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↓,

2726- BetA,    Betulinic acid induces DNA damage and apoptosis in SiHa cells
- in-vitro, Cerv, SiHa
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

2733- BetA,    Betulinic Acid Inhibits Cell Proliferation in Human Oral Squamous Cell Carcinoma via Modulating ROS-Regulated p53 Signaling
- in-vitro, Oral, KB - in-vivo, NA, NA
TumCP↓, BA dose-dependently inhibited KB cell proliferation and decreased implanted tumor volume.
TumVol↓,
mt-Apoptosis↑, BA significantly promoted mitochondrial apoptosis, as reflected by an increase in TUNEL+ cells and the activities of caspases 3 and 9, an increase in Bax expression, and a decrease in Bcl-2 expression and the mitochondrial oxygen consumption rate.
Casp3↑,
Casp9↑,
BAX↑,
Bcl-2↑,
OCR↓, BA dose-dependently decreased the oxygen consumption rate, indicating that BA induced a significant mitochondrial dysfunction
TumCCA↑, BA significantly increased cell population in the G0/G1 phase and decreases the S phase cell number, indicating the occurrence of G0/G1 cell cycle arrest.
ROS↑, ROS generation was significantly increased by BA
eff↓, and antioxidant NAC treatment markedly inhibited the effect of BA on apoptosis, cell cycle arrest, and proliferation.
P53↑, BA dose-dependently increased p53 expression in KB cells and implanted tumors.
STAT3↓, Inhibition of STAT3 Signaling Is Involved in BA-Induced Suppression of Cell Proliferation
cycD1↑, We found that BA mainly increased the mRNA expression of cyclin D1 but had no significant effect on cyclin E, CDK2, CDK4, or CDK6 expression.

2737- BetA,    Multiple molecular targets in breast cancer therapy by betulinic acid
- Review, Var, NA
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: 10

Results for Effect on Cancer/Diseased Cells:
p‑Akt↓,1,   angioG↓,1,   AntiCan↑,1,   Apoptosis↓,1,   Apoptosis↑,4,   mt-Apoptosis↑,2,   BAD↑,1,   BAX↑,3,   Bax:Bcl2↑,1,   Bcl-2↓,3,   Bcl-2↑,1,   Bcl-xL↓,1,   Casp↑,1,   Casp3↑,5,   Casp7↑,1,   Casp8↑,2,   Casp9↑,6,   CDC25↓,1,   CDK2↓,1,   ChemoSen↑,1,   Cyc↓,1,   cycA1↓,2,   CycB↓,2,   cycD1↑,1,   Cyt‑c↑,3,   DNAdam↑,1,   eff↓,4,   eff↑,2,   EMT↓,1,   FTH1↓,1,   GCLM↓,1,   GLUT1↓,1,   GSTA1↓,1,   GSTs↓,1,   Half-Life↝,1,   JNK↑,1,   LAMs↓,1,   lipid-P↑,1,   MAPK↑,1,   Mcl-1↓,1,   MDA↑,1,   MMP↓,8,   MMP9↓,1,   MMPs↓,1,   mtDam↑,1,   NF-kB↓,6,   OCR↓,1,   P21↑,2,   p27↑,1,   p38↑,1,   P53↑,1,   PARP↓,1,   cl‑PARP↑,2,   cl‑PARP1↑,1,   PDK1↓,1,   PI3K↓,1,   RadioS↑,1,   ROS↓,1,   ROS↑,7,   ROS∅,1,   i-ROS↑,1,   selectivity↑,2,   Slug↓,1,   Snail↓,1,   SOD↓,1,   SOD2↓,1,   Sp1/3/4↓,2,   STAT3↓,2,   TOP1↓,4,   TumCCA↑,10,   TumCD↑,2,   TumCI↓,1,   TumCMig↓,1,   TumCP↓,2,   tumCV↓,1,   TumVol↓,2,   VEGF↓,3,  
Total Targets: 77

Results for Effect on Normal Cells:
antiOx↑,1,   hepatoP↑,1,   Inflam↓,1,   ROS↓,1,  
Total Targets: 4

Scientific Paper Hit Count for: TumCCA, Tumor cell cycle arrest
10 Betulinic acid
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:42  Target#:322  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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