Gambogic Acid / mTOR Cancer Research Results

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

Gambogic acid — a naturally occurring, highly prenylated caged xanthone isolated principally from gamboge resin produced by Garcinia hanburyi. It is an experimental small-molecule anticancer agent commonly abbreviated GA or GBA, with the molecular formula C38H44O8. GA is an electrophilic, multi-target compound whose α,β-unsaturated carbonyl groups can covalently modify reactive cysteine residues in redox-regulatory and proteostasis proteins. It has undergone limited Phase I and Phase IIa clinical investigation in China as an intravenous formulation but is not an established or broadly approved anticancer drug.

Primary mechanisms (ranked):

  1. Covalent inhibition of thioredoxin and thioredoxin reductase, with additional inhibition of PRDX1 and related thiol-dependent antioxidant systems, causing collapse of tumor-cell redox buffering.
  2. ROS accumulation followed by mitochondrial membrane depolarization, cytochrome-c release, Bax/Bcl-2 imbalance, caspase activation, apoptosis, and in some models GSDME-dependent pyroptosis.
  3. Covalent inhibition of 6-phosphogluconate dehydrogenase, suppressing the oxidative pentose phosphate pathway, NADPH generation, and antioxidant regeneration.
  4. Disruption of thiol proteostasis, proteasome function, HSP90-dependent client-protein stability, and endoplasmic-reticulum homeostasis, producing ER stress, unfolded-protein responses, autophagy, paraptosis, or apoptosis.
  5. Suppression of PI3K–AKT–mTOR, NF-κB, STAT3, survivin, and other pro-survival signaling pathways.
  6. Cell-cycle arrest through context-dependent activation of p53 and p21 and suppression of cyclin D1 and related proliferative regulators.
  7. Inhibition of angiogenesis, invasion, and metastasis through reduced HIF-1α, VEGF, MMP-2, MMP-9, and epithelial–mesenchymal transition signaling.
  8. Chemosensitization and reversal of multidrug resistance through inhibition of P-glycoprotein, survivin, NF-κB, and stress-adaptation pathways; radiosensitization has also been reported preclinically.

Bioavailability / PK relevance: GA is highly lipophilic, poorly water-soluble, chemically reactive, and rapidly distributed and metabolized. Human studies have used intravenous GA formulations rather than conventional oral dosing. A major circulating human metabolite is 10-hydroxygambogic acid. Short systemic persistence, formulation-dependent exposure, local irritation, and limited aqueous solubility have driven extensive investigation of liposomes, albumin carriers, polymeric nanoparticles, solid-lipid nanoparticles, and other targeted delivery systems. Preclinical toxicology identifies the liver and kidney as principal dose-limiting target organs, with potential drug-interaction concerns related to CYP3A4 and transporter modulation.

In-vitro vs systemic exposure relevance: Many mechanistic studies use approximately micromolar GA concentrations and short, direct cellular exposure. These conditions may produce greater free-drug exposure than is safely sustained in plasma or tissues because GA is poorly soluble, extensively protein-bound, rapidly metabolized, and systemically toxic at higher exposure. Covalent target engagement may permit biological activity despite transient exposure, but concentration-dependent cell-culture findings should not be assumed to translate directly to achievable unencapsulated systemic dosing.

Clinical evidence status: Predominantly preclinical, with limited small-human evidence. An open-label, randomized, multicentre Phase IIa study evaluated different intravenous dosing schedules in patients with advanced solid malignancies and reported mainly grade 1–2 adverse effects, but the study was small, lacked a placebo or standard-treatment control, and did not establish definitive efficacy. There is no robust confirmatory randomized trial evidence, no established survival benefit, and no routine clinical role. GA should therefore be classified as an investigational natural-product-derived anticancer agent rather than an approved chemotherapy.

Gambogic Acid Mechanistic Ranking

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Thioredoxin and thioredoxin reductase inhibition ↓ Trx1, Trx2 and TrxR activity ↓ antioxidant capacity possible P Redox-buffering collapse Core electrophilic mechanism involving covalent modification of catalytic or regulatory cysteine residues.
2 Peroxiredoxin and thiol proteostasis ↓ PRDX1 function; ↓ thiol proteostasis Potential oxidative and proteotoxic injury P–R Loss of peroxide detoxification and protein homeostasis PRDX1 has been identified as a direct covalent target; target relevance may vary by tumor type.
3 Reactive oxygen species accumulation ↑ ROS ↑ ROS at sufficient exposure P–R Oxidative-stress overload Central downstream consequence of antioxidant-system inhibition; not inherently cancer-selective.
4 Pentose phosphate pathway and 6PGD ↓ 6PGD; ↓ PPP; ↓ NADPH ↓ NADPH possible R Metabolic and antioxidant restriction GA covalently inhibits 6PGD, limiting NADPH production and reinforcing oxidative stress.
5 Mitochondrial membrane integrity ↓ membrane potential; ↑ cytochrome c release Mitochondrial toxicity possible R Intrinsic apoptosis initiation Frequently linked to ROS, p53, Bax activation, and Bcl-2 suppression.
6 Apoptosis and pyroptosis execution ↑ caspase-3, caspase-8 and caspase-9; ↑ GSDME cleavage Cell death possible at toxic exposure R–G Programmed cell death Predominantly apoptosis; GSDME-dependent pyroptosis occurs in selected GSDME-expressing models.
7 Endoplasmic reticulum stress and unfolded-protein response ↑ PERK, ATF6, GRP78 and CHOP signaling ER stress possible R–G Proteotoxic stress and apoptosis Usually secondary to ROS accumulation, covalent protein modification, and proteostasis disruption.
8 Proteasome and HSP90 chaperone function ↓ proteasome activity; ↓ HSP90 client stability Proteostasis toxicity possible R–G Oncoprotein destabilization May reduce AKT, HER2, survivin, and other short-lived or chaperone-dependent proteins.
9 PI3K AKT mTOR survival signaling ↓ PI3K; ↓ p-AKT; ↓ mTOR Context-dependent suppression R–G Reduced growth and stress adaptation May be partly downstream of oxidative stress and degradation of signaling proteins.
10 NF-κB and STAT3 signaling ↓ NF-κB; ↓ STAT3; ↓ survivin ↓ inflammatory signaling possible R–G Reduced survival and inflammatory transcription Contributes to apoptosis, reduced invasion, and sensitization to cytotoxic therapy.
11 Cell-cycle checkpoints ↑ p53 and p21; ↓ cyclin D1; ↑ arrest Growth arrest possible G Proliferation blockade Checkpoint and arrest phase vary among tumor models.
12 Autophagy and paraptosis ↑ autophagy; ↑ vacuolization; ↑ paraptosis Context-dependent stress response G Adaptive or non-apoptotic cell death Autophagy may be protective or cytotoxic; chloroquine can enhance GA activity in some models.
13 HIF-1α VEGF angiogenesis axis ↓ HIF-1α; ↓ VEGF; ↓ angiogenesis Potential impairment of physiological angiogenesis G Reduced tumor vascular support Preclinical effect; systemic antiangiogenic selectivity is not established.
14 Invasion and metastasis ↓ MMP-2; ↓ MMP-9; ↓ migration; ↓ EMT Limited direct evidence G Reduced invasive phenotype Likely integrates NF-κB, PI3K–AKT, HIF-1α, and cytoskeletal signaling effects.
15 Chemosensitization and drug resistance ↓ P-gp; ↓ survivin; ↑ chemotherapy sensitivity ↑ combination toxicity possible G Resistance reversal Synergy reported with doxorubicin, cisplatin, docetaxel, chloroquine, and other agents in preclinical models.
16 Radiosensitization ↑ radiation-induced ROS and cell death Potential ↑ normal-tissue radiation injury R–G Enhanced radiation response Preclinical and context-dependent; therapeutic selectivity remains uncertain.
17 Clinical Translation Constraint Exposure limited by solubility, metabolism, formulation and heterogeneity Kidney, liver and local irritation risks G Restricted therapeutic window Poor aqueous solubility, short systemic persistence, covalent off-target activity, CYP and transporter interactions, and weak controlled clinical evidence limit translation.

P: 0–30 min    R: 30 min–3 hr    G: >3 hr



older table (left here for references)
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)


mTOR, mammalian target of rapamycin: Click to Expand ⟱
Source: HalifaxProj (inhibit)
Type:
mTOR (mechanistic target of rapamycin) is a central regulator of cell growth, proliferation, metabolism, and survival. It is a serine/threonine kinase that integrates signals from nutrients, growth factors, and cellular energy status.
mTOR promotes protein synthesis and cell growth by activating downstream targets such as S6 kinase and 4E-BP1. In cancer, this pathway can become hyperactivated, leading to uncontrolled cell proliferation.

mTor Inhibitors:
-rapamycin (Sirolimus): classic natural product mTOR inhibitor
-Curcumin
-Resveratrol
-Epigallocatechin Gallate (EGCG)
-Honokiol
Scientific Papers found: Click to Expand⟱
5151- GamB,    Gambogic acid affects ESCC progression through regulation of PI3K/AKT/mTOR signal pathway
- in-vitro, ESCC, KYSE-30 - in-vitro, ESCC, KYSE450
TumCP↓, GA treatment caused an inhibition in ESCC cell proliferation, migration and invasion.
TumCMig↓,
TumCI↓,
Apoptosis↑, GA induced dose-dependent apoptosis of ESCC cells, repressed the expression of Bcl2 and up-regulated the levels of Bax protein, cleaved-PARP1 and cleaved-caspase 3/9.
Bcl-2↓,
BAX↑,
cl‑PARP1↑,
cl‑Casp3↑,
cl‑Casp9↑,
PI3K↓, GA down-regulated the levels of PI3K, p-AKT and p-mTOR, while promoted PTEN expression in ESCC cells.
p‑Akt↓,
p‑mTOR↓,
PTEN↑, A may down-regulate PI3K/AKT/mTOR pathway through activating PTEN

5152- GamB,    Gambogic Acid as a Candidate for Cancer Therapy: A Review
- Review, Var, NA
AntiCan↑, GA has obvious anti-cancer effects via various molecular mechanisms, including the induction of apoptosis, autophagy, cell cycle arrest and the inhibition of invasion, metastasis, angiogenesis.
Apoptosis↑,
TumAuto↑,
TumCCA↑,
TumCI↓,
TumMeta↓,
angioG↓,
eff↑, In order to improve the efficacy in cancer treatment, nanometer drug delivery systems have been employed to load GA and form micelles, nanoparticles, nanofibers
NF-kB↓, GA could inhibit the activation of NF-κB
P53↑, GA increases p53 expression via down-regulating MDM2 in wild type p53 expressing human cancer cells (non-small cell lung H1299)
P21↑, GA could enhance p21Waf1/CIP1 expression to induce cell apoptosis in human breast cancer cells (MCF-7) via suppressing MDM2
MDM2↓,
HSP90↓, GA was considered as a natural product inhibitor of Hsp90
Bcl-2↓, bcl-2 reduction is associated with the release of cytochrome c, leading to an apoptosis cascade reaction
Cyt‑c↑,
Casp↑,
MMP↓, rapid mitochondrial membrane depolarization and fragmentation
Casp3↑, activation of caspase-3, 9 and cleaved PARP and increased ratio of bax/bcl-2.
Casp9↑,
cl‑PARP↑,
Bax:Bcl2↑,
ROS↑, GA-induced reactive oxygen species (ROS) may be the cause of the collapse of mitochondrial transmembrane potential, which could also down-regulate SIRT1 in multiple myeloma
SIRT1↓,
TrxR1↓, GA may also interact with the thioredoxin reductase 1 (TrxR1) to elicit oxidative stress leading to ROS accumulation in hepatocellular carcinoma
Fas↓, GA with increased death receptor (Fas, FasL, Fas-associated protein with death domain (FADD) and Apaf-1) and deoxyribonucleic acid (DNA) fragmentation.
FasL↑,
FADD↑,
APAF1↑,
DNAdam↑,
NF-kB↓, GA could inhibit NF-κB pathway through suppressing IκBα and p65 phosphorylation
STAT3↓, GA also suppressed the signal transducer and activator of transcription (STAT3) phosphorylation to induce cell apoptosis
MAPK↓, GA induced cell apoptosis via suppression of mitogen-activated protein kinases (MAPK) pathway and c-fos
cFos↓,
EGFR↓, GA could also enhance epidermal growth factor receptor (EGFR) degradation and inhibit AKT/mTOR complex 1 (mTORC1) via up-regulating AMP-activated protein kinase (AMPK)-
Akt↓,
mTOR↓,
AMPK↑,
TumCCA↑, GA could obviously induce G2/M or G0/G1 arrest in various cancer cell lines, such as MCF-7 cells, K562 cells, U2OS cells, and so on
ChemoSen↑, GA distinctly sensitized doxorubicin (DOX)-resistant breast cancer cells through inhibiting P-glycoprotein and suppressing the survivin expression revealed by ROS-mediated activation of the p38 MAPK
P-gp/ABCB1↓,
survivin↓,

7065- GamB,    Gambogic acid: A review of its pharmacological mechanisms against cancer
- Review, Var, NA
AntiTum↑, Preclinical studies demonstrate that GA exerts broad-spectrum antitumor effects through multiple mechanisms: induction of apoptosis via mitochondrial and death receptor pathways;
Apoptosis↑,
TumCCA↑, cell cycle arrest at G0/G1 or G2/M phases;
angioG↓, inhibition of angiogenesis via HIF-1α/VEGF/MMPs suppression;
Hif1a↓,
VEGF↓,
MMPs↓,
TumMeta↓, reduction of metastasis through downregulation of MMPs.
NF-kB↓, GA modulates key oncogenic pathways including NF-κB, PI3K/Akt/mTOR, and MAPKs. Several studies report an inhibitory effect of GA on NF-κB signaling
PI3K↓, inhibiting the phosphorylation (activation) of Akt and mTOR, thereby suppressing the PI3K/Akt/mTOR signaling cascade
Akt↓,
mTOR↓,
MAPK↓, this study linked the anti-invasive effect to the inhibition of MAPK signaling
P-gp/ABCB1↓, targeting P-glycoprotein, Bcr-Abl, and SHH pathways. This dual action of inhibiting both P-gp function/expression and a key signaling pathway (NF-κB) driving resistance makes GA a particularly attractive agent for tackling MDR.
Shh↓, GA’s downregulation of the SHH signaling pathway
Pyro↑, GA induces immunogenic pyroptosis via caspase-3/GSDME activation
Casp3↑,
GSDME↑,
ChemoSen↑, Synergistic effects are observed when GA is combined with chemotherapy, targeted agents (e.g., bortezomib, gefitinib), radiotherapy, or photothermal therapy.
RadioS↑,
BioAv↓, However, GA’s clinical application is limited by poor solubility and bioavailability.
Bcl-2↓, decrease in the expression of anti-apoptotic proteins like Bcl-2 and Mcl-1, coupled with an increase in pro-apoptotic proteins like Bax,
Mcl-1↓,
BAX↑,
Half-Life↓, GA can exhibit a short half-life in circulation, limiting its exposure time at the tumor site
ROS↑, As mentioned earlier, the generation of reactive oxygen species (ROS) appears to be a significant factor in GA’s action in multiple cancer types
miR-21↓, GA treatment counteracted this process; it reduced miR-21 levels in tumor cells
MMP2↓, GA decreased both the protein levels (Western blotting, immunocytochemistry) and the enzymatic activities (gelatin zymography) of MMP-2 and MMP-9.
MMP9↓,

1969- GamB,    Gambogic acid promotes apoptosis and resistance to metastatic potential in MDA-MB-231 human breast carcinoma cells
- in-vitro, BC, MDA-MB-231 - in-vivo, NA, NA
AntiTum↑, (GA) is considered a potent anti-tumor agent for its multiple effects on cancer cells in vitro and in vivo
TumCI↓, Low concentrations of GA (0.3-1.2 µmol/L) can suppress invasion of human breast carcinoma cells without affecting cell viability
Apoptosis↑, GA (3 and 6 µmol/L) induced apoptosis in MDA-MB-231 cells and the accumulation of reactive oxygen species (ROS).
ROS↑,
Cyt‑c↑, release of cytochrome c (Cyt c) from mitochondria
Akt↓, GA also inhibited cell survival via blocking Akt/mTOR signaling
mTOR↓,
TumCG↓, In vivo, GA significantly inhibited the xenograft tumor growth and lung metastases in athymic BALB/c nude mice bearing MDA-MB-231 cells.
TumMeta↓,


Showing Research Papers: 1 to 4 of 4

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 4

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

ROS↑, 3,   TrxR1↓, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

AMPK↑, 1,   SIRT1↓, 1,  

Cell Death(tgid=5) ⓘ

APAF1↑, 1,   Apoptosis↑, 4,   BAX↑, 2,   Bax:Bcl2↑, 1,   Bcl-2↓, 3,   Casp↑, 1,   Casp3↑, 2,   cl‑Casp3↑, 1,   Casp9↑, 1,   cl‑Casp9↑, 1,   Cyt‑c↑, 2,   FADD↑, 1,   Fas↓, 1,   FasL↑, 1,   GSDME↑, 1,   Mcl-1↓, 1,   MDM2↓, 1,   Pyro↑, 1,   survivin↓, 1,  

Kinase & Signal Transduction(tgid=6) ⓘ

Akt↓, 3,   p‑Akt↓, 1,   EGFR↓, 1,   MAPK↓, 2,   mTOR↓, 3,   p‑mTOR↓, 1,   PI3K↓, 2,   PTEN↑, 1,   STAT3↓, 1,  

Transcription & Epigenetics(tgid=7) ⓘ

miR-21↓, 1,  

Protein Folding & ER Stress(tgid=8) ⓘ

HSP90↓, 1,  

Autophagy & Lysosomes(tgid=9) ⓘ

TumAuto↑, 1,  

DNA Damage & Repair(tgid=10) ⓘ

DNAdam↑, 1,   P53↑, 1,   cl‑PARP↑, 1,   cl‑PARP1↑, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

P21↑, 1,   TumCCA↑, 3,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

cFos↓, 1,   Shh↓, 1,   TumCG↓, 1,   TumCP↓, 1,  

Migration(tgid=13) ⓘ

MMP2↓, 1,   MMP9↓, 1,   MMPs↓, 1,   TumCI↓, 3,   TumCMig↓, 1,   TumMeta↓, 3,  

Angiogenesis & Vasculature(tgid=14) ⓘ

angioG↓, 2,   Hif1a↓, 1,   VEGF↓, 1,  

Barriers & Transport(tgid=15) ⓘ

MMP↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

NF-kB↓, 3,  

Drug Metabolism & Resistance(tgid=21) ⓘ

BioAv↓, 1,   ChemoSen↑, 2,   eff↑, 1,   Half-Life↓, 1,   P-gp/ABCB1↓, 2,   RadioS↑, 1,  

Clinical Biomarkers(tgid=22) ⓘ

EGFR↓, 1,  

Functional Outcomes(tgid=23) ⓘ

AntiCan↑, 1,   AntiTum↑, 2,  
Total Targets: 65

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: mTOR, mammalian target of rapamycin
4 Gambogic 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#:302  Target#:209  State#:%  Dir#:1
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