Deguelin / TumCI Cancer Research Results

Deg, Deguelin: Click to Expand ⟱
Features: Insect poisoning, anti-cancer
Deguelin is a natural compound of isoflavonoid-derived rotenoid isolated from several plant species, including Derris trifoliata Lour and Mundulea sericea (Leguminosae) (4)

Deguelin’s ability to modulate multiple signaling pathways—including PI3K/Akt, mTOR, NF-κB, HIF-1α, and MAPK
While preclinical studies have utilized dosages in the approximate range of 4–8 mg/kg in animal models, these figures are specific to the experimental conditions and species used in those studies.

Deguelin is a rotenoid (isoflavonoid-like botanical insecticide class) found in some Lonchocarpus / Derris species. In cancer literature it’s most often described as a mitochondrial Complex I inhibitor with downstream energy stress + survival pathway suppression (Akt/PI3K, NF-κB) and apoptosis/autophagy induction. A major caution is neurotoxicity signal: rotenoids (including deguelin) have been used in Parkinson’s disease animal models via Complex I inhibition.
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Active identity: Rotenoid (deguelin) — a potent mitochondrial Complex I inhibitor with downstream energy-stress signaling (AMPK/mTOR), survival pathway suppression (Akt, NF-κB), and apoptosis/autophagy induction in cancer models; higher caution category due to rotenoid neurotoxicity signals in animal models.

Deguelin — a naturally occurring rotenoid derived principally from leguminous plants in the Derris, Lonchocarpus, Tephrosia, and related genera. It is a lipophilic isoflavonoid-related botanical insecticide and experimental anticancer small molecule, commonly abbreviated Deg. Its functional identity is dominated by mitochondrial respiratory Complex I inhibition, with secondary suppression of Hsp90-dependent oncogenic proteins and PI3K/AKT, NF-κB, mTOR, HIF-1α, angiogenic, and metastatic signaling. Deguelin is not an approved anticancer drug and has a substantial translational safety concern because systemic exposure can injure dopaminergic neurons and produce Parkinsonism-like pathology in animals.

Primary mechanisms (ranked):

  1. Mitochondrial electron-transport-chain Complex I inhibition, causing reduced oxidative phosphorylation, ATP depletion, energetic stress, and context-dependent ROS accumulation.
  2. Direct or functionally relevant disruption of Hsp90 chaperone activity, destabilizing oncogenic client proteins including AKT, HIF-1α, survivin, and CDK4.
  3. PI3K/AKT survival-axis suppression, contributing to reduced proliferation, survival signaling, invasion, and treatment resistance.
  4. AMPK activation with downstream mTOR and survivin suppression in energy-stressed cancer cells.
  5. Intrinsic mitochondrial apoptosis through mitochondrial membrane dysfunction, cytochrome-c release, caspase activation, and PARP cleavage.
  6. NF-κB pathway suppression through reduced IKK activation and inflammatory or anti-apoptotic transcription.
  7. HIF-1α and VEGF suppression, reducing hypoxic adaptation, angiogenesis, and lymphangiogenesis.
  8. Cell-cycle arrest through reduced cyclins, CDKs, and oncogenic Hsp90 clients, with context-dependent increases in p21 or p27.
  9. Inhibition of migration, epithelial–mesenchymal transition, invasion, and metastasis through context-dependent modulation of c-MET, EGFR, STAT3, MAPK, MMP2, MMP9, and related pathways.
  10. Autophagy induction or modulation, which may be cytotoxic or adaptive depending on tumor type, dose, and treatment duration.

Bioavailability / PK relevance: Deguelin is highly lipophilic and poorly suited to simple aqueous delivery. Rat pharmacokinetic studies found measurable systemic persistence and a relatively long plasma residence time, but human pharmacokinetics, oral bioavailability, therapeutic exposure targets, metabolism, and safe dosing have not been established. Formulation research has therefore focused on analogues, nanoparticles, and other delivery systems intended to improve solubility or tumor exposure. Enhanced delivery could also increase neurological and systemic toxicity.

In-vitro vs systemic exposure relevance: Anticancer effects are frequently reported from low-nanomolar to several-micromolar concentrations, depending on the cell model and endpoint. Some sensitive models respond below 0.1 µM, whereas apoptosis, ROS, autophagy, or broad cytotoxicity studies commonly use approximately 1–20 µM. There is no validated human exposure range demonstrating that these concentrations can be achieved safely. Because mitochondrial Complex I inhibition occurs in normal as well as malignant tissue, systemic exposure cannot be assumed to preserve cancer selectivity.

Clinical evidence status: Preclinical only. Evidence consists primarily of biochemical studies, cancer-cell experiments, xenografts, chemically induced tumor models, and rodent metastasis or chemoprevention studies. No established human anticancer trial evidence, approved indication, clinically validated dose, or accepted adjunct regimen was identified. Neurotoxicity and delivery limitations currently outweigh the strength of the efficacy evidence for clinical translation.



Deguelin Mechanistic Profile

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Mitochondrial Complex I and oxidative phosphorylation Complex I ↓; oxygen consumption ↓; ATP ↓; energetic stress ↑ Complex I ↓; mitochondrial function ↓; neurotoxicity risk ↑ P, R Bioenergetic inhibition Central pharmacological action. PTEN-deficient and mitochondrially vulnerable tumors may show increased sensitivity, but inhibition is not tumor-specific.
2 Hsp90 chaperone and oncogenic client stability Hsp90 function ↓; AKT ↓; survivin ↓; CDK4 ↓; HIF-1α ↓ Protein-homeostasis disruption ↑ (dose-dependent) R, G Oncoprotein destabilization Deguelin has been reported to bind Hsp90 and disrupt client-protein complexes. Structural derivatives have been developed to retain this activity while reducing toxicity.
3 PI3K and AKT survival signaling PI3K/AKT ↓; p-AKT ↓; proliferation ↓; survival ↓ AKT signaling ↓ (context-dependent) R, G Growth and survival suppression A recurrent mechanism across lung, breast, colon, pancreatic, and other experimental cancer models.
4 AMPK and mTOR energy-sensing axis AMPK ↑; mTOR ↓; protein synthesis ↓; survivin ↓ AMPK ↑; mTOR ↓ (energy-stress dependent) R, G Metabolic growth restriction Likely downstream in part from mitochondrial ATP depletion and altered AMP-to-ATP balance.
5 Mitochondrial ROS and redox stress ROS ↑; oxidative damage ↑; apoptosis sensitivity ↑ ROS ↑; oxidative neuronal injury risk ↑ P, R Redox-mediated cytotoxicity ROS contribution is model-dependent. Antioxidants such as N-acetylcysteine partially reverse apoptosis in some studies.
6 Intrinsic mitochondrial apoptosis Mitochondrial membrane potential ↓; cytochrome-c release ↑; caspase-9 ↑; caspase-3 ↑; PARP cleavage ↑ Apoptosis ↑ at toxic exposure G Programmed cell death Common downstream outcome of Complex I inhibition, ROS elevation, Hsp90-client loss, and AKT suppression.
7 NF-κB inflammatory and survival transcription IKK ↓; IκB degradation ↓; NF-κB activity ↓; anti-apoptotic transcription ↓ Inflammatory signaling ↓ (context-dependent) R, G Anti-inflammatory and pro-apoptotic signaling Reported against constitutive and stimulus-induced NF-κB activation.
8 HIF-1α and angiogenic signaling HIF-1α ↓; VEGF ↓; hypoxic adaptation ↓; angiogenesis ↓ Physiological hypoxia responses may ↓ at systemic exposure R, G Anti-angiogenic activity May reflect Hsp90-client destabilization, AKT inhibition, and altered mitochondrial oxygen sensing.
9 Cell-cycle regulation G1 or S-phase arrest ↑; cyclins ↓; CDKs ↓; p21 or p27 ↑ Proliferation ↓ at sufficient exposure G Cytostasis Exact arrest point and regulatory proteins vary among cancer models.
10 Autophagy and stress adaptation Autophagy ↑ (context-dependent); autophagic death or survival adaptation ↑ Autophagy ↑ (context-dependent) G Stress-response modulation The functional consequence must be experimentally determined; autophagy is not uniformly anticancer.
11 Migration invasion and epithelial–mesenchymal transition c-MET ↓; EGFR ↓; STAT3 ↓; ERK ↓; MMP2 ↓; MMP9 ↓; EMT ↓; migration ↓ ↔ or tissue-repair signaling ↓ (context-dependent) G Anti-metastatic activity Mechanisms differ substantially by cancer lineage and may be secondary to reduced viability or Hsp90-client destabilization.
12 NRF2 antioxidant response NRF2 ↔ or ↑ (secondary, model-dependent) NRF2 ↑ may partially compensate for oxidative stress R, G Adaptive redox response NRF2 is not a consistently established primary deguelin target. Direction and therapeutic significance should not be generalized across models.
13 Chemosensitization and radiosensitization Treatment sensitivity ↑ (model-dependent); survival and HIF-1α signaling ↓ Normal-tissue toxicity may ↑ R, G Adjunct sensitization Preclinical reports support sensitization in selected models, but no clinically validated combination or therapeutic window exists.
14 Clinical Translation Constraint Potential tumor exposure limited by solubility, formulation, heterogeneity, and uncertain therapeutic window Complex I inhibition; dopaminergic neuron injury; Parkinsonism-like toxicity; possible systemic mitochondrial toxicity R, G Major development barrier No approved formulation, validated human PK, established safe dose, or demonstrated human efficacy. Delivery enhancement does not remove mechanism-based neurotoxicity.

P: 0–30 min    R: 30 min–3 hr    G: >3 hr
TumCI, Tumor Cell invasion: Click to Expand ⟱
Source:
Type:
Tumor cell invasion is a critical process in cancer progression and metastasis, where cancer cells spread from the primary tumor to surrounding tissues and distant organs. This process involves several key steps and mechanisms:

1.Epithelial-Mesenchymal Transition (EMT): Many tumors originate from epithelial cells, which are typically organized in layers. During EMT, these cells lose their epithelial characteristics (such as cell-cell adhesion) and gain mesenchymal traits (such as increased motility). This transition is crucial for invasion.

2.Degradation of Extracellular Matrix (ECM): Tumor cells secrete enzymes, such as matrix metalloproteinases (MMPs), that degrade the ECM, allowing cancer cells to invade surrounding tissues. This degradation facilitates the movement of cancer cells through the tissue.

3.Cell Migration: Once the ECM is degraded, cancer cells can migrate. They often use various mechanisms, including amoeboid movement and mesenchymal migration, to move through the tissue. This migration is influenced by various signaling pathways and the tumor microenvironment.

4.Angiogenesis: As tumors grow, they require a blood supply to provide nutrients and oxygen. Tumor cells can stimulate the formation of new blood vessels (angiogenesis) through the release of growth factors like vascular endothelial growth factor (VEGF). This not only supports tumor growth but also provides a route for cancer cells to enter the bloodstream.

5.Invasion into Blood Vessels (Intravasation): Cancer cells can invade nearby blood vessels, allowing them to enter the circulatory system. This step is crucial for metastasis, as it enables cancer cells to travel to distant sites in the body.

6.Survival in Circulation: Once in the bloodstream, cancer cells must survive the immune response and the shear stress of blood flow. They can form clusters with platelets or other cells to evade detection.

7.Extravasation and Colonization: After traveling through the bloodstream, cancer cells can exit the circulation (extravasation) and invade new tissues. They may then establish secondary tumors (metastases) in distant organs.

8.Tumor Microenvironment: The surrounding microenvironment plays a significant role in tumor invasion. Factors such as immune cells, fibroblasts, and signaling molecules can either promote or inhibit invasion and metastasis.
Scientific Papers found: Click to Expand⟱
19- Deg,    Deguelin inhibits proliferation and migration of human pancreatic cancer cells in vitro targeting hedgehog pathway
- in-vitro, PC, Bxpc-3 - in-vitro, PC, PANC1
HH↓, Gli1↓, PTCH1↓, Sufu↓, MMP2↓, MMP9↓, PI3K/Akt↓, HIF-1↓, VEGF↓, IKKα↓, NF-kB↓, EMT↓, AMPK↑, mTOR↓, survivin↓, TumCG↓, Apoptosis↑, TumCMig↓, TumCI↓,
6673- Deg,    Deguelin, an Akt inhibitor, suppresses IkappaBalpha kinase activation leading to suppression of NF-kappaB-regulated gene expression, potentiation of apoptosis, and inhibition of cellular invasion
NF-kB↓, IKKα↓, TNFR 1↓, TumCP↓, TumCI↓,

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:


Core Metabolism/Glycolysis(tgid=4) ⓘ

AMPK↑, 1,   PI3K/Akt↓, 1,  

Cell Death(tgid=5) ⓘ

Apoptosis↑, 1,   survivin↓, 1,   TNFR 1↓, 1,  

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

EMT↓, 1,   Gli1↓, 1,   HH↓, 1,   mTOR↓, 1,   PTCH1↓, 1,   Sufu↓, 1,   TumCG↓, 1,  

Migration(tgid=13) ⓘ

MMP2↓, 1,   MMP9↓, 1,   TumCI↓, 2,   TumCMig↓, 1,   TumCP↓, 1,  

Angiogenesis & Vasculature(tgid=14) ⓘ

HIF-1↓, 1,   VEGF↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

IKKα↓, 2,   NF-kB↓, 2,  
Total Targets: 21

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: TumCI, Tumor Cell invasion
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#:69  Target#:324  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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