Auranofin / mTOR Cancer Research Results

AF, Auranofin: Click to Expand ⟱
Features:

Auranofin — an orally administered gold(I) coordination complex (gold–phosphine–thiolate “thiosugar” drug) originally approved as a disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis and widely studied for repurposing as a redox-targeted anticancer and anti-infective agent. It is a small-molecule metallodrug whose pharmacology is typically tracked via blood/plasma gold concentrations because intact auranofin is rapidly transformed and not reliably detected in blood. Standard abbreviation(s): AF (auranofin); primary target shorthand: TrxR/TxNRD (thioredoxin reductase).

Primary mechanisms (ranked):

  1. Thioredoxin reductase (TXNRD1/TXNRD2; TrxR) inhibition by gold(I) → thioredoxin system suppression and loss of redox-buffering capacity
  2. ROS and redox stress escalation (secondary to TrxR blockade; often NAC-reversible in models) → apoptosis and other regulated death programs
  3. Mitochondrial dysfunction (Δψm collapse, bioenergetic stress) coupled to redox imbalance
  4. Proteostasis stress (ER stress/UPR; proteasome involvement in selected contexts) → non-apoptotic death phenotypes (model-dependent)
  5. Ferroptosis contribution in subsets of models (lipid peroxidation–dependent; context-dependent)
  6. Radiosensitization / chemosensitization via impaired antioxidant recovery and enhanced oxidative injury (context-dependent)
  7. Stress-response transcription (e.g., NRF2 activation as an adaptive resistance program in some settings; protective in normal cells)

Bioavailability / PK relevance: Oral absorption is incomplete; clinical PK is commonly described as ~25% of the gold content absorbed. Gold is highly protein-bound and exhibits prolonged retention/long terminal half-life, so effective exposure depends strongly on dose and dosing duration. Because “gold levels” are the main measurable surrogate, cross-study comparisons should specify matrix (whole blood vs plasma) and timing (steady-state vs short course).

In-vitro vs systemic exposure relevance: Many oncology cell studies use ~0.5–5 µM AF. Human short-course data at 6 mg/day for 7 days report plasma gold on the order of ~0.1–0.3 µg/mL (roughly sub-µM to ~1–1.5 µM range when expressed as gold equivalents), meaning lower in-vitro ranges can overlap clinically observed exposure surrogates, while higher µM regimens may exceed typical oral exposures unless higher doses/longer courses or formulation changes are used.

Clinical evidence status: Approved for rheumatoid arthritis (historical DMARD use) but oncology use remains investigational. Multiple early-phase repurposing trials exist across hematologic and solid tumors; several completed studies have limited publicly posted outcomes, and there is no established standard-of-care anticancer indication.


Pathways:
1.Thioredoxin Reductase (TrxR) Inhibition.
- Most widely recognized for potently inhibiting TrxR.
2.Induction of Reactive Oxygen Species (ROS) and Oxidative Stress.
3.MMP depolarization, release of cytochrome c
4.Endoplasmic Reticulum (ER) Stress and Unfolded Protein Response (UPR)
5.Inhibition of Pro-survival Pathways (e.g., NF-κB Signaling)

-ic50 for cancer typically 1-3uM, normal cell 5-10uM or higher.
-Several studies animal testing antitumor efficacy have used doses in the region of 5–8 mg/kg via intraperitoneal injection or oral administration.

-Auranofin’s anticancer activity is often linked to its inhibition of thioredoxin reductase, leading to increased oxidative stress.

Mechanistic axes for Auranofin (Cancer vs Normal)

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 TXNRD1 TXNRD2 Thioredoxin system ↓ (primary) ↓ (primary) P→R Collapse of thioredoxin redox buffering Core, proximal target of AF; downstream effects track with redox reserve and compensatory antioxidant capacity rather than tumor lineage alone.
2 ROS redox stress ↑ (often primary downstream) ↑ (dose-dependent) P→R Oxidative injury signaling and death pathway engagement Frequently reversible with thiol antioxidants (e.g., NAC) in models, supporting causality; magnitude depends on baseline redox fragility.
3 Mitochondria bioenergetics Δψm ↓, ATP stress ↑ (context-dependent) Δψm ↓ (dose-dependent) R Energetic crisis and intrinsic death susceptibility Often coupled to redox imbalance; can amplify apoptosis/regulated necrosis depending on cellular checkpoints.
4 Proteostasis ER stress UPR ↑ (model-dependent) ↔/↑ (high exposure only) R→G Protein-folding overload and non-apoptotic death phenotypes Some reports implicate proteasome participation and paraptosis-like outcomes; not universal across tumor types.
5 NRF2 antioxidant response ↑ (adaptive; resistance role) ↑ (cytoprotective) R→G Transcriptional compensation to redox stress NRF2 induction can blunt AF efficacy in tumors yet protect normal tissues; net effect is (context-dependent).
6 Ferroptosis lipid peroxidation ↑ (model-dependent) ↔/↑ (stress-prone contexts) R→G Regulated death component in subsets Most consistent when AF-driven redox stress converges on lipid ROS handling; requires model-specific validation.
7 Radiosensitization chemosensitization ↑ sensitivity (context-dependent) ↑ toxicity risk (context-dependent) R→G Impaired antioxidant recovery increases treatment injury Mechanistically coherent with TrxR blockade; best supported where oxidative damage markers and combination indices are shown.
8 Ca²⁺ stress coupling ↑/↔ (secondary) ↑/↔ (secondary) R Amplifies ER mitochondrial death signaling Usually downstream of redox + organelle perturbation; include when Ca²⁺-dependent apoptosis/ER stress is explicitly demonstrated.
9 Glycolysis ATP production ↓ (context-dependent) ↔/↓ (high exposure only) R Metabolic stress that can reduce proliferative fitness Reported in some models; may be secondary to mitochondrial/redox disruption rather than a primary binding target.
10 HIF-1α hypoxia programs ↔ (model-dependent) ↔ G Context marker rather than core axis Evaluate case-by-case; AF’s primary leverage is redox enzyme inhibition, with HIF effects emerging indirectly in some systems.
11 Clinical Translation Constraint ↔ ↔ — Exposure, tolerability, and selectivity limit window Oral absorption is incomplete and gold is long-retained/protein-bound; many oncology studies rely on µM in-vitro dosing that may exceed typical oral exposure surrogates. Oncology trials exist but anticancer efficacy is not established as standard-of-care.

TSF legend: P: 0–30 min | R: 30 min–3 hr | G: >3 hr
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⟱
5462- AF,    Repurposing Auranofin for Oncology and Beyond: A Brief Overview of Clinical Trials as Mono- and Combination Therapy
- Review, Var, NA
AntiTum↑, Over the last twenty years, AF has also been repurposed as an antitumor, antiviral, and antibacterial drug.
Bacteria↓,
TrxR↓, ability to inhibit thioredoxin reductase (TrxR) and disrupt redox homeostasis, leading to selective cytotoxicity in cancer cells.
ChemoSen↑, synergistic effects observed when AF is combined with chemotherapeutics, targeted therapies, or immune modulators.
Dose↝, Patients received AF orally twice daily on days 1–28. atients received AF orally, 6 mg in the morning and 6 mg in the evening.
ROS↑, AF induces oxidative stress and apoptosis in cancer cells by disrupting redox homeostasis, while sirolimus inhibits mTOR signaling.
Apoptosis↑,
mTOR↓,

5468- AF,    The gold complex auranofin: new perspectives for cancer therapy
- Review, Var, NA
TrxR↓, Auranofin mainly targets the anti-oxidative system catalyzed by thioredoxin reductase (TrxR), which protects the cell from oxidative stress and death in the cytoplasm and the mitochondria.
ROS↑, Inhibiting TrxR dysregulates the intracellular redox state causing increased intracellular reactive oxygen species levels, and stimulates cellular demise
eff↑, TrxR is over-expressed in many cancers as an adaptive mechanism for cancer cell proliferation, rendering it an attractive target for cancer therapy, and auranofin as a potential therapeutic agent for cancer.
Apoptosis↑, promotion of ASK-induced apoptosis, and blockage of cell growth, proliferation, and survival due to reduced AKT activity and NF-kB- and p53-mediated transcription.
TumCG↓,
TumCP↓,
Akt↓,
NF-kB↓,
DNAdam↑, DNA damage
eff↝, auranofin inhibits TrxR1 in a p53-independent manner
eff↓, Pre-treatment with NAC counteracted the cancer cell killing effects of auranofin,
PI3K↓, auranofin induces cytotoxicity in human pancreatic adenocarcinoma and non-small cell lung cancer via the inhibition of the PI3K/AKT/mTOR pathway
Akt↓,
mTOR↓,
Hif1a↓, auranofin inhibits the cancer cell response to hypoxia, demonstrated by a decrease in HIF-1 𝛼 expression and VEGF secretion upon auranofin treatment under hypoxic conditions
VEGF↓,
Casp3↑, auranofin was shown to induce caspase-3-mediated apoptosis in human ovarian carcinoma SKOV-3 cells
CSCs↓,
ATP↓, it was found that auranofin inhibits ABCG2 function by depleting cellular ATP via inhibition of glycolysis [96]
Glycolysis↓,
Synergy↑, auranofin synergizes with another Trx1 inhibitor, piperlongumine, in killing gastric cancer cells in association with ROS-mediated ER stress response and mitochondrial dysfunction.
eff↑, when the gold complex is combined with either selenite or tellurite [104]
MMP↓, Increased ROS induced by AUR causes decreased membrane potential in the mitochondrial membrane, resulting in a decrease in anti-apoptotic proteins, caspase-dependent cell death, and translocation of apoptosis-inducing factor (AIF)
AIF↑,
toxicity↓, Auranofin is considered safe for human use in treating rheumatoid arthritis; thus, this gold derivative can reach the clinic for other diseases relatively quickly and at a low cost


Showing Research Papers: 1 to 2 of 2

* 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(tgid=1) ⓘ

ROS↑, 2,   TrxR↓, 2,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

ATP↓, 1,   Glycolysis↓, 1,  

Cell Death(tgid=5) ⓘ

AIF↑, 1,   Apoptosis↑, 2,   Casp3↑, 1,  

Kinase & Signal Transduction(tgid=6) ⓘ

Akt↓, 2,   mTOR↓, 2,   PI3K↓, 1,  

DNA Damage & Repair(tgid=10) ⓘ

DNAdam↑, 1,  

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

CSCs↓, 1,   TumCG↓, 1,   TumCP↓, 1,  

Angiogenesis & Vasculature(tgid=14) ⓘ

Hif1a↓, 1,   VEGF↓, 1,  

Barriers & Transport(tgid=15) ⓘ

MMP↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

NF-kB↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

ChemoSen↑, 1,   Dose↝, 1,   eff↓, 1,   eff↑, 2,   eff↝, 1,   Synergy↑, 1,  

Functional Outcomes(tgid=23) ⓘ

AntiTum↑, 1,   toxicity↓, 1,  

Infection & Microbiome(tgid=24) ⓘ

Bacteria↓, 1,  
Total Targets: 27

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: mTOR, mammalian target of rapamycin
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#:273  Target#:209  State#:%  Dir#:1
  wNotes=on  sortOrder:rid,rpid

 

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