Disulfiram / NRF2 Cancer Research Results

DSF, Disulfiram: Click to Expand ⟱
Features:
Disulfiram is a synthetic small-molecule drug best known for its use in the treatment of chronic alcohol use disorder. It is a thiuram disulfide compound with the chemical formula C₁₀H₂₀N₂S₄ and acts primarily as an aldehyde dehydrogenase (ALDH) inhibitor. 
Main Actions:
-Potent copper-dependent pro-oxidant
-Targets ALDH⁺ cancer stem cells
-Strong clinical repurposing interest

Key pathways
-Cu-mediated redox cycling
-Proteasome inhibition
-Mitochondrial ROS

Chemo relevance
-Often synergistic
-Highly mechanism-dependent
Rank Pathway / Axis Cancer Cells Normal Cells Label Primary Interpretation Notes
1 Metal chelation / Disulfiram–Cu complex formation ↑ DSF–Cu complex formation ↔ limited formation Driver Copper-dependent cytotoxic chemistry Elevated copper in cancer cells enables formation of cytotoxic DSF–Cu complexes; this is the initiating event for most anticancer effects
2 Proteasome / p97–NPL4 axis ↓ proteasome function; ↑ proteotoxic stress ↔ minimal disruption Driver Protein homeostasis collapse DSF–Cu disrupts protein degradation pathways, leading to accumulation of misfolded proteins and stress signaling
3 Reactive oxygen species (ROS) ↑ ROS (metal-dependent) ↔ buffered Secondary Oxidative stress amplification ROS rise follows DSF–Cu redox cycling and proteotoxic stress; not the primary trigger
4 Mitochondrial integrity / intrinsic apoptosis ↓ ΔΨm; ↑ caspase activation ↔ preserved Secondary Execution of cell death Mitochondrial dysfunction and apoptosis occur downstream of proteostasis and redox stress
5 ALDH activity (ALDH1A1 / stemness) ↓ ALDH activity ↓ ALDH (clinically tolerated) Secondary Cancer stem-like cell targeting ALDH inhibition preferentially impacts cancer stem-like populations; normal cells tolerate inhibition at therapeutic exposure
6 NF-κB signaling ↓ NF-κB activation ↓ inflammatory NF-κB tone Secondary Suppression of survival transcription NF-κB inhibition reflects upstream proteotoxic and redox stress rather than direct targeting
7 Cell cycle progression ↓ proliferation / ↑ arrest ↔ largely spared Phenotypic Cytostatic growth control Growth inhibition reflects impaired protein turnover and metabolic stress
8 Apoptosis / non-apoptotic death ↑ apoptosis or proteotoxic death ↔ protected Phenotypic Threshold-dependent cell death Cell death modality depends on copper availability and stress magnitude


NRF2, nuclear factor erythroid 2-related factor 2: Click to Expand ⟱
Source: TCGA
Type: Antiapoptotic
Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress. Thought of as "Master Regulator" of antioxidant response.
-One way to estimate Nrf2 induction is through the expression of NQO1.
NQO1, the most potent inducer:
SFN 0.2 μM,
quercetin (2.5 μM),
curcumin (2.7 μM),
Silymarin (3.6 μM),
tamoxifen (5.9 μM),
genistein (6.2 μM ),
beta-carotene (7.2μM),
lutein (17 μM),
resveratrol (21 μM),
indol-3-carbinol (50 μM),
chlorophyll (250 μM),
alpha-cryptoxanthin (1.8 mM),
and zeaxanthin (2.2 mM)

1. Raising Nrf2 enhances the cell's antioxidant defenses and ↓ROS. This strategy is used to decrease chemo-radio side effects.
2. Downregulating Nrf2 lowers antioxidant defenses and ↑ROS. In cancer cells this leads to DNA damage, and cell death.
3. However there are some cases where increasing Nrf2 paradoxically causes an increase in ROS (cancer cells). Such as cases of Mitochondial overload, signal crosstalk, reductive stress

-In some cases, Nrf2 is overexpressed in cancer cells, which can lead to the activation of genes involved in cell proliferation, angiogenesis, and metastasis. This can contribute to the development of resistance to chemotherapy and targeted therapies.
-Increased Nrf2 expression: Lung, Breast, Colorectal, Prostrate.
Decreased Nrf2 expression: Skine, Liver, Pancreatic.
-Nrf2 is a cytoprotective transcription factor which demonstrated both a negative effect as well as a positive effect on cancer
- "promotes Nrf2 translocation from the cytoplasm to the nucleus," means facilitates the movement of Nrf2 into the nucleus, thereby enhancing the cell's antioxidant and cytoprotective responses. -Major regulator of Nrf2 activity in cells is the cytosolic inhibitor Keap1.

Nrf2 Inhibitors and Activators
Nrf2 Inhibitors: Brusatol, Luteolin, Trigonelline, VitC, Retinoic acid, Chrysin
Nrf2 Activators: SFN, OPZ EGCG, Resveratrol, DATS, CUR, CDDO, Api
- potent Nrf2 inducers from plants include sulforaphane, curcumin, EGCG, resveratrol, caffeic acid phenethyl ester, wasabi, cafestol and kahweol (coffee), cinnamon, ginger, garlic, lycopene, rosemany

Nrf2 plays dual roles in that it can protect normal tissues against oxidative damage and can act as an oncogenic protein in tumor tissue.
– In healthy tissues, NRF2 activation helps protect cells from oxidative damage and maintains cellular homeostasis.
– In many cancers, constitutive activation of NRF2 (often through mutations in NRF2 itself or loss-of-function mutations in KEAP1) leads to an enhanced antioxidant capacity.
– This upregulation can promote tumor cell survival by enabling cancer cells to thrive under oxidative stress, resist chemotherapeutic agents, and sustain metabolic reprogramming.
– Elevated NRF2 levels have been implicated in promoting tumor growth, metastasis, and resistance to therapy in various malignancies.
– High or sustained NRF2 activity is frequently associated with aggressive tumor phenotypes, poorer prognosis, and decreased overall survival in several cancer types.
– While its activation is essential for protecting normal cells from oxidative stress, aberrant or sustained NRF2 activation in tumor cells can lead to enhanced survival, therapeutic resistance, and tumor progression.

NRF2 inhibitors: (to decrease antioxidant defenses and increase cell death from ROS).
-Brusatol: most cited natural inhibitors of Nrf2.
-Luteolin: luteolin can reduce Nrf2 activity in specific cancer models and may enhance cell sensitivity to chemotherapy. However, luteolin is also known as an antioxidant, and its influence on Nrf2 can sometimes be context dependent.
-Apigenin: certain studies to down‑regulate Nrf2 in cancer cells: Dose and context dependent .
-Oridonin:
-Wogonin: although its effects might be cell‑ and dose‑specific.
- Withaferin A

Scientific Papers found: Click to Expand⟱
5006- DSF,  Cu,    Disulfiram targeting lymphoid malignant cell lines via ROS-JNK activation as well as Nrf2 and NF-kB pathway inhibition
- vitro+vivo, lymphoma, NA
TumCD↑, TumCP↑, Apoptosis↑, NRF2↓, ROS↑, p‑JNK↑, p65↓, eff↓, NF-kB↓,
5007- DSF,  Cu,    Nrf2/HO-1 Alleviates Disulfiram/Copper-Induced Ferroptosis in Oral Squamous Cell Carcinoma
- vitro+vivo, Oral, NA
AntiTum↑, TumCP↓, Ferroptosis↑, Iron↑, lipid-P↑, NRF2↓, HO-1↓,
5009- DSF,  Cu,    Activation of Oxidative Stress and Down-Regulation of Nuclear Factor Erythroid 2-Related Factor May Be Responsible for Disulfiram/Copper Complex Induced Apoptosis in Lymphoid Malignancy Cell Lines
- vitro+vivo, lymphoma, NA
AntiTum↑, ROS↑, JNK↑, NRF2↓, eff↓, TumCD↑,

Showing Research Papers: 1 to 3 of 3

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 3

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Ferroptosis↑, 1,   HO-1↓, 1,   Iron↑, 1,   lipid-P↑, 1,   NRF2↓, 3,   ROS↑, 2,  

Cell Death ⓘ

Apoptosis↑, 1,   Ferroptosis↑, 1,   JNK↑, 1,   p‑JNK↑, 1,   TumCD↑, 2,  

Migration ⓘ

TumCP↓, 1,   TumCP↑, 1,  

Immune & Inflammatory Signaling ⓘ

NF-kB↓, 1,   p65↓, 1,  

Drug Metabolism & Resistance ⓘ

eff↓, 2,  

Functional Outcomes ⓘ

AntiTum↑, 2,  
Total Targets: 17

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: NRF2, nuclear factor erythroid 2-related factor 2
3 Disulfiram
3 Copper and Cu NanoParticles
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#:387  Target#:226  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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