Database Query Results : Gambogic Acid, , Trx

GamB, Gambogic Acid: Click to Expand ⟱
Features:
Gambogic acid is a naturally occurring xanthonoid extracted from the resin of trees belonging to the Garcinia genus—most notably, Garcinia hanburyi. This tree is native to regions in Southeast Asia, particularly found in areas of China, India, and neighboring countries.
Gambogic acid (GA; C38H44O8, MW: 628.76), a polyprenylated xanthone and a widely used coloring agent, is the main active ingredient of gamboges secreted from the Garcinia hanburyi tree ([3, 4], which mainly grows in Southeast Asia.
GA has been approved by the Chinese FDA for the treatment of solid cancers in Phase II clinical trials.

Pathways:
-evidence suggesting that it can inhibit thioredoxin reductase (TrxR).
-can indeed lead to an increase in reactive oxygen species (ROS) levels
-Gambogic acid can trigger mitochondrial dysfunction, leading to cytochrome c release
-influences death receptors
-Inhibition of NF-κB Signaling
-Inhibition of VEGF Pathway
-Cell Cycle Arrest:
-p53 Activation
Rank Pathway / Target Axis Direction Primary Effect Notes / Cancer Relevance Ref
1 Thioredoxin / Thioredoxin reductase (Trx / TrxR) ↓ Trx / TrxR activity Redox buffering collapse Primary molecular target; covalent cysteine interaction drives loss of antioxidant capacity (ref)
2 ROS accumulation ↑ ROS Oxidative stress overload Immediate consequence of Trx/TrxR inhibition; upstream of mitochondrial damage (ref)
3 Mitochondrial integrity (ΔΨm) ↓ ΔΨm Mitochondrial dysfunction GA reduces mitochondrial membrane potential prior to execution-phase death (ref)
4 Intrinsic apoptosis / pyroptosis (caspase-3, GSDME) ↑ programmed cell death Execution-phase killing Mitochondrial apoptosis and caspase-3/GSDME-dependent pyroptosis reported (ref)
5 NF-κB signaling ↓ NF-κB activation Reduced pro-survival transcription Redox-sensitive suppression of NF-κB nuclear activity and target genes (ref)
6 PI3K–AKT survival signaling ↓ AKT phosphorylation Survival pathway collapse Downstream of oxidative stress and chaperone disruption (ref)
7 HSP90 chaperone function ↓ client stabilization Oncoprotein destabilization GA disrupts HSP90–client interactions affecting AKT, HER2, etc. (ref)
8 ER stress / UPR ↑ ER stress signaling Proteotoxic stress Secondary ER stress response following redox and mitochondrial disruption (ref)
9 Cell cycle regulation ↑ cell-cycle arrest Proliferation blockade Checkpoint activation downstream of stress signaling (ref)
10 Autophagy (stress-induced) ↑ autophagy Adaptive or pro-death response Autophagy induction reported; role varies by context (ref)
11 Angiogenesis signaling (VEGF) ↓ VEGF expression Anti-angiogenic effect Suppression of pro-angiogenic transcription observed (ref)
12 Tumor growth in vivo ↓ tumor volume Integrated outcome Xenograft models show significant tumor growth inhibition (ref)


Trx, Thioredoxin: Click to Expand ⟱
Source:
Type: protein
Trx is a small protein that acts as a reducing agent, donating electrons to reduce oxidized proteins and other molecules.
Trx is overexpressed in various types of cancer, including breast, lung, colon, and prostate cancer.

- Cytosolic thioredoxin (TRX-1) and mitochondrial thioredoxin (TRX-2).

- Thioredoxin is a pivotal redox regulator that protects cells from oxidative stress and supports survival and proliferation.

- There is interest in combining thioredoxin inhibitors with conventional chemotherapy or radiotherapy to sensitize tumors to oxidative stress and improve treatment efficacy.
Scientific Papers found: Click to Expand⟱
1973- GamB,    Gambogic acid deactivates cytosolic and mitochondrial thioredoxins by covalent binding to the functional domain
- in-vitro, Liver, SMMC-7721 cell
Apoptosis↑, selectively induces apoptosis in cancer cells, at least partially, by targeting the stress response to reactive oxygen species (ROS).
ROS↑,
Trx↓, deactivates TRX-1/2 proteins by covalent binding to the active cysteine residues in the functional domain via Michael addition reactions.
Trx1↓,
Trx2↓,
Mich↑, can react with small nucleophilic molecules, such as GSH and a cysteine-containing peptide, via a Michael addition reaction.

1955- GamB,    Gambogic acid inhibits thioredoxin activity and induces ROS-mediated cell death in castration-resistant prostate cancer
- in-vitro, Pca, PC3 - in-vitro, Pca, LNCaP - in-vitro, Pca, DU145
ROS↑, GA disrupted cellular redox homeostasis, observed as elevated reactive oxygen species (ROS), leading to apoptotic and ferroptotic death.
Apoptosis↑,
Ferroptosis↑,
Trx↓, GA inhibited thioredoxin
eff↑, Auranofin (AUR), a thioredoxin reductase (TrxR) inhibitor was the one compound that demonstrated additive growth inhibition together with GA when both were combined at sub-thresh hold concentrations
TrxR↓, GA may inhibit the thioredoxin (Trx) system, which mainly composes NADPH, TrxR, and Trx.
Dose∅, GA demonstrated sub-micromolar activity (IC50 = 185nM) which was 50 times more potent than the next most active compounds, curcumin and tanshinone (CT)
MMP↓, GA treatment showed increasing loss of membrane polarity at 4 and 6 hours in PCAP-1 cells
eff↑, GA enhanced the cell killing observed for either docetaxel (DOX) or enzalutamide (ENZA)
Casp↑, These results suggest that GA initiates CASP-dependent death of PCAP-1 cells and that both iron-dependent oxidative injury and direct CASP activation contribute
NADPH↓, These results suggest that GA may inhibit the thioredoxin (Trx) system, which mainly composes NADPH, TrxR, and Trx.
TrxR↓,
ChemoSen↑, potential use of GA in combination with standard chemotherapeutic (docetaxel) and anti-androgen endocrine (enzalutamide) therapies for advanced PrCa.
AR↓, inhibit PrCa growth, in part by inhibiting AR signaling


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

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Ferroptosis↑, 1,   Mich↑, 1,   ROS↑, 2,   Trx↓, 2,   Trx1↓, 1,   Trx2↓, 1,   TrxR↓, 2,  

Mitochondria & Bioenergetics ⓘ

MMP↓, 1,  

Core Metabolism/Glycolysis ⓘ

NADPH↓, 1,  

Cell Death ⓘ

Apoptosis↑, 2,   Casp↑, 1,   Ferroptosis↑, 1,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 1,  

Drug Metabolism & Resistance ⓘ

ChemoSen↑, 1,   Dose∅, 1,   eff↑, 2,  

Clinical Biomarkers ⓘ

AR↓, 1,  
Total Targets: 17

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: Trx, Thioredoxin
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#:302  Target#:824  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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