Disulfiram / p65 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

Disulfiram — a synthetic thiuram disulfide small molecule clinically used as an alcohol-deterrent drug. It is formally classified as an aldehyde dehydrogenase inhibitor and drug-repurposing candidate; standard abbreviations are DSF and, historically, Antabuse. Following administration, DSF is rapidly converted to diethyldithiocarbamate and other metabolites. In cancer models, the most compelling activity is generally attributed not to direct ALDH inhibition by parent DSF, but to formation of the copper-containing metabolite bis(diethyldithiocarbamate)-copper, commonly termed CuET or DSF–Cu. CuET preferentially accumulates under some tumour-associated conditions and disrupts protein homeostasis by targeting the NPL4 adaptor of the p97/VCP segregase.

Primary mechanisms (ranked):

  1. Copper-dependent CuET formation and aggregation of NPL4, disabling the p97/VCP segregase and producing severe proteotoxic stress.
  2. Disruption of ubiquitin-dependent protein processing, replication-fork maintenance and DNA-damage responses, including impaired ATR-pathway signaling.
  3. Oxidative and mitochondrial stress, including increased ROS, loss of mitochondrial membrane potential and activation of apoptotic or non-apoptotic cell death.
  4. Suppression of tumour-cell survival programs, including NF-κB, AKT and context-dependent MAPK signaling.
  5. Ferroptosis sensitization through ROS, glutathione depletion and lipid peroxidation; NRF2 and HO-1 can provide adaptive resistance rather than serving as a uniformly inhibited primary target.
  6. Inhibition of cancer stem-like phenotypes and ALDH activity, although ALDH inhibition is not considered the principal explanation for CuET-mediated anticancer cytotoxicity.
  7. Chemosensitization and radiosensitization through proteotoxic stress, defective DNA-damage repair and increased oxidative injury.

Bioavailability / PK relevance: Oral DSF is absorbed but undergoes extensive and variable first-pass metabolism and rapid conversion into diethyldithiocarbamate, methylated metabolites, carbon disulfide and downstream sulfur-containing products. Parent DSF is therefore an unreliable systemic exposure marker. Anticancer translation depends on production, distribution and tumour delivery of CuET or related copper complexes; oral copper supplementation does not guarantee therapeutically adequate intratumoural CuET and introduces additional toxicity and pharmacologic variability.

In-vitro vs systemic exposure relevance: Many experiments add micromolar DSF and excess copper directly to culture medium, allowing rapid extracellular CuET formation. These conditions may substantially exceed or poorly reproduce the concentrations, copper speciation, protein binding and metabolite distribution achieved after conventional oral DSF. Results obtained with DSF–Cu or preformed CuET should not be interpreted as equivalent to exposure from standard DSF dosing.

Clinical evidence status: Extensive preclinical evidence and several small phase I or phase II oncology studies are available, including combinations with chemotherapy, radiotherapy or copper. A small randomized NSCLC study reported a possible survival signal, but subsequent glioblastoma trials were negative or insufficiently active, and the overall clinical evidence remains inconsistent. Disulfiram is not approved by FDA, Health Canada or EMA as an anticancer therapy. Any oncology use, particularly with copper supplementation, remains investigational and should occur within a clinical trial.

Major safety constraints: Alcohol exposure can produce a potentially severe disulfiram–ethanol reaction and must be avoided during treatment and for up to 14 days after discontinuation. Important risks include hepatitis or liver failure, peripheral neuropathy, optic neuritis, psychiatric reactions and clinically significant interactions with metronidazole, warfarin, phenytoin and several CYP-metabolized drugs. Baseline and follow-up hepatic monitoring are important. Added copper may increase gastrointestinal, hepatic and neurologic toxicity and should not be regarded as a benign supplement in an oncology regimen.



Disulfiram Mechanistic Profile

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Copper-dependent CuET formation ↑ CuET formation and accumulation ↔ or ↑ exposure (context-dependent) P–R Generation of the principal cytotoxic species DSF metabolites chelate copper to form CuET; extracellular copper concentration, protein binding and cellular copper handling strongly determine activity.
2 NPL4 and p97/VCP segregase ↓ NPL4 function; ↑ NPL4 aggregation ↓ at sufficient exposure P–R Collapse of ubiquitin-dependent protein processing CuET immobilizes NPL4 and disrupts p97/VCP-mediated extraction and turnover of ubiquitinated proteins. This is the best-supported direct anticancer target.
3 Proteostasis and unfolded protein stress ↑ ubiquitinated proteins; ↑ proteotoxic stress ↑ at cytotoxic exposure R–G Loss of protein homeostasis and cell viability Frequently described as proteasome inhibition, but much of the effect may arise upstream through NPL4 and p97/VCP disruption rather than direct catalytic proteasome blockade.
4 Replication stress and ATR response ↑ stalled forks; ↑ DNA damage; ↓ ATR signaling ↑ damage at sufficient exposure R–G Defective replication-fork protection and checkpoint signaling BRCA1-deficient, BRCA2-deficient or replication-stressed cells may be especially vulnerable (model-dependent).
5 Mitochondrial ROS increase ↑ ROS and oxidative injury ↑ ROS (dose-dependent) P–R Amplification of proteotoxic and mitochondrial stress ROS is an important downstream or parallel mechanism but is not necessarily the initiating molecular event.
6 Mitochondrial membrane integrity ↓ membrane potential; ↓ ATP; ↑ cytochrome c release ↓ at cytotoxic exposure R–G Intrinsic apoptotic signaling Mitochondrial dysfunction is reported across several tumour models, especially with added copper.
7 NRF2 and antioxidant adaptation ↑ or ↓ NRF2 (context-dependent) ↑ antioxidant response (context-dependent) R–G Determination of oxidative-stress sensitivity or resistance Some models show NRF2 suppression, whereas others show compensatory NRF2 and HO-1 activation that protects against DSF–Cu-induced ferroptosis. A single fixed direction is not justified.
8 Glutathione and ferroptosis ↓ GSH; ↑ lipid peroxidation; ↑ ferroptosis ↔ or ↑ oxidative injury R–G Iron-dependent oxidative cell death Prominent in selected tumour models and enhanced when NRF2, HO-1 or glutathione defenses are impaired.
9 NF-κB survival signaling ↓ NF-κB activation ↓ inflammatory signaling (context-dependent) R–G Reduced survival and inflammatory transcription May reflect altered proteostasis, redox signaling or inhibition of upstream regulatory protein turnover rather than a single direct binding interaction.
10 AKT and MAPK signaling ↓ AKT; ↑ or ↓ MAPK signaling (model-dependent) ↔ or ↓ signaling R–G Suppression of proliferation and survival MAPK direction varies by tumour type, exposure and sampling time; stress-associated JNK activation commonly accompanies apoptosis.
11 ALDH and cancer stem-like state ↓ ALDH activity; ↓ stem-like phenotype ↓ ALDH activity R–G Potential depletion of ALDH-high tumour populations Biologically relevant in some models, but ALDH inhibition should not be presented as the dominant CuET anticancer mechanism.
12 Cell cycle progression ↓ proliferation; ↑ G1 or G2/M arrest ↓ proliferation at sufficient exposure G Cytostatic response preceding cell death Cell-cycle outcome varies with tumour genotype, copper availability and treatment duration.
13 Apoptosis and proteotoxic cell death ↑ caspase-dependent and non-apoptotic death ↑ toxicity at high exposure G Terminal execution of accumulated cellular stress The mode of death depends on copper, redox state, NRF2 capacity, genotype and treatment combination.
14 Chemosensitization ↑ sensitivity to DNA-damaging agents and selected proteostasis-targeting drugs ↑ combination toxicity possible G Lowered tolerance of treatment-induced damage Reported with platinum agents, temozolomide and other drugs, but clinical efficacy has not been consistently reproduced.
15 Radiosensitization ↑ radiation response (model-dependent) ↑ radiation injury possible G Enhanced oxidative, DNA and proteotoxic damage Supported by preclinical studies and early clinical testing; tumour selectivity and optimal copper exposure remain unresolved.
16 Clinical Translation Constraint ↔ variable tumour CuET exposure ↑ hepatic, neurologic and drug-interaction risk G Uncertain correspondence between laboratory activity and oral dosing Rapid metabolism, variable bioavailability, copper speciation, formulation, intratumoural delivery, heterogeneous trial designs and mostly small or negative studies currently limit translation.

P: 0–30 min    R: 30 min–3 hr    G: >3 hr
p65, RelA: Click to Expand ⟱
Source:
Type:
P65, also known as RelA, is a subunit of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) transcription factor complex. NF-κB plays a crucial role in regulating immune response, inflammation, and cell survival.
Due to its role in cancer progression, p65 and the NF-κB pathway are considered potential therapeutic targets. Inhibitors of NF-κB signaling are being explored in preclinical and clinical studies as potential cancer treatments.
Many studies have reported that p65 is overexpressed in various types of cancers, including breast, prostate, lung, and colorectal cancers.
In some cancers, elevated p65 levels correlate with higher grades of tumors and advanced stages of disease.

"RELA proto-oncogene, NF-κB subunit." It encodes the p65 protein, which is a central component of the NF‑κB transcription factor complex.
-Chronic activation of RELA and the NF‑κB pathway is frequently associated with cancer progression, promoting inflammation-driven tumorigenesis, chemoresistance, and metastasis.
-RELA interacts with other oncogenic signaling networks (for example, STAT3 and MAPK pathways), further integrating environmental signals that favor cancer progression.

RELA (p65) is a critical subunit of the NF‑κB transcription factor complex, involved in the regulation of genes that control inflammation, cell survival, and proliferation. In the context of cancer, aberrant activation and overexpression of RELA are frequently associated with aggressive tumor behavior, therapy resistance, and poorer patient outcomes in cancers such as breast, lung, colorectal, and pancreatic cancers, among others.

RELA emerges as a potential key contributor to the suppression of glycolysis, mitochondrial respiration, and ATP production in cancer cells. (RELA knockdown signifcantly reduced the tumorigenic.
potential of various pancreatic cancer cell lines).
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↓,

Showing Research Papers: 1 to 1 of 1

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress(tgid=1) ⓘ

NRF2↓, 1,   ROS↑, 1,  

Cell Death(tgid=5) ⓘ

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

Migration(tgid=13) ⓘ

TumCP↑, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

NF-kB↓, 1,   p65↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

eff↓, 1,  
Total Targets: 9

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: p65, RelA
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#:238  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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