Evodiamine / COX2/PTGS2 Cancer Research Results

EVO, Evodiamine: Click to Expand ⟱
Features:
Evodiamine is a bioactive alkaloid isolated primarily from the fruit of the traditional Chinese medicinal herb Evodia rutaecarpa. Evodiamine is a natural alkaloid from Evodia rutaecarpa, a traditional Chinese medicine. It has various pharmacological activities, such as anti-inflammatory, anti-cancer, anti-microbial and metabolic regulation, but also shows hepatotoxicity and cardiotoxicity.

Evodiamine — a naturally occurring quinazolinocarboline indole alkaloid isolated mainly from the dried, immature fruit of Tetradium ruticarpum, historically known as Evodia rutaecarpa or Evodiae Fructus. It is classified as an experimental plant-derived small molecule and multitarget anticancer lead compound. Standard abbreviations include EVO, EVD and EDM. Evodiamine interacts with topoisomerases, microtubules, mitochondrial death pathways and several oncogenic signalling networks, but it is not an approved anticancer drug and has extremely poor oral bioavailability.

Primary mechanisms (ranked):

  1. Disruption of DNA topology through inhibition or trapping of topoisomerase I and catalytic inhibition of topoisomerase II, producing replication stress, DNA damage signalling and cell-cycle arrest.
  2. Mitotic disruption through altered tubulin polymerization and microtubule dynamics, commonly producing G2/M or mitotic arrest.
  3. Induction of mitochondrial and endoplasmic-reticulum-associated apoptosis through mitochondrial membrane depolarization, Bax/Bcl-2 modulation, cytochrome-c release and caspase activation.
  4. Suppression of PI3K/AKT/mTOR and related survival signalling, with context-dependent activation of stress MAPKs including JNK and p38.
  5. ROS elevation and oxidative stress that amplify mitochondrial dysfunction, DNA damage and apoptosis in susceptible cancer cells.
  6. Suppression of NF-κB and STAT3 transcriptional signalling, reducing anti-apoptotic, inflammatory, angiogenic and metastatic gene expression.
  7. Inhibition of HSP70-mediated proteostasis and survival of cancer stem-like and chemoresistant cell populations.
  8. Suppression of invasion, EMT, angiogenesis and immune-evasion signalling, including context-dependent reductions in MMP-9, VEGF, MUC1-C and PD-L1.
  9. Induction of autophagy, which may be cytotoxic or cytoprotective depending on cancer type, concentration and treatment duration.

Bioavailability / PK relevance: Native evodiamine is poorly water-soluble, has limited gastrointestinal absorption, undergoes extensive metabolism and has exceptionally low systemic oral bioavailability in animal models; an approximate oral bioavailability of 0.1% has been reported in rats. Nanoparticles, phospholipid complexes, solid dispersions, liposomes and structural analogues improve exposure experimentally, but no optimized formulation has established clinical anticancer efficacy.

In-vitro vs systemic exposure relevance: Most anticancer experiments use micromolar evodiamine concentrations maintained for hours to days. These exposures substantially exceed the plasma concentrations expected after conventional oral evodiamine because of its poor dissolution, absorption and systemic availability. Direct translation of common cell-culture concentrations to oral supplementation is therefore not pharmacokinetically supported.

Clinical evidence status: Preclinical only. Anticancer evidence consists primarily of cell-culture studies, xenografts and other animal models. No established randomized clinical trial evidence demonstrates efficacy against cancer, and evodiamine has no FDA, EMA or Health Canada approval as an anticancer therapy. Hepatotoxicity, cardiotoxicity, formulation limitations and uncertain human pharmacokinetics remain major development barriers.


Evodiamine Mechanistic Profile

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Topoisomerase I and II TOP1-DNA cleavage complexes ↑; TOP1 and TOP2 activity ↓; DNA damage ↑ DNA damage possible ↑ at sufficient exposure R–G Replication stress, DNA strand damage and growth inhibition Evodiamine has been reported as a TOP1 poison or cleavage-complex stabilizer and as a dual TOP1/TOP2 catalytic inhibitor; the precise mode is assay-dependent.
2 Tubulin and mitotic progression Tubulin polymerization altered; G2/M arrest ↑; mitotic arrest ↑ Mitotic toxicity possible ↑ in proliferating normal cells R–G Failure of mitotic progression Microtubule disruption may explain the frequent G2/M phenotype better than TOP1 inhibition alone.
3 Mitochondrial apoptosis Mitochondrial membrane potential ↓; Bax ↑; Bcl-2 and Bcl-xL ↓; cytochrome c ↑; caspase-9 and caspase-3 ↑ Mitochondrial toxicity possible ↑ (dose-dependent) R–G Intrinsic apoptotic cell death One of the most consistently reproduced downstream effects across cancer models.
4 PI3K AKT mTOR survival signalling PI3K ↓; p-AKT ↓; mTOR signalling ↓ Variable or insufficiently characterized R–G Reduced survival, proliferation and therapy resistance Observed in glioma, pancreatic, hepatic, prostate and other cancer models; not necessarily a direct molecular target.
5 Mitochondrial ROS and oxidative stress ROS ↑; oxidative damage ↑; mitochondrial dysfunction ↑ Oxidative injury possible ↑ at toxic concentrations P–R Amplification of apoptosis and cell-cycle arrest ROS dependence is model-dependent; antioxidant rescue has been reported in selected systems. This is not evidence of cancer-selective oxidative stress in humans.
6 Stress MAPK signalling JNK ↑; p38 ↑; ERK variable Variable or insufficiently characterized P–R Stress signalling, mitotic arrest and apoptosis MAPK direction varies by cell type and exposure; JNK activation is mechanistically important in several colorectal and mitochondrial-apoptosis models.
7 NF-κB inflammatory and survival signalling IKK activity ↓; IκBα degradation ↓; NF-κB activation ↓; COX-2 ↓; anti-apoptotic proteins ↓ Inflammatory signalling ↓ (context-dependent) R–G Reduced survival, inflammation, invasion and chemoresistance NF-κB suppression can sensitize experimental tumors to gemcitabine and other cytotoxic treatments.
8 SHP-1 STAT3 axis SHP-1 ↑; STAT3 Tyr705 phosphorylation ↓; cyclin D1, survivin, XIAP, VEGF and MMP-9 ↓ Insufficiently characterized R–G Reduced proliferation, angiogenesis and survival Strongly demonstrated in hepatocellular carcinoma models but may not generalize uniformly across cancers.
9 HSP70 proteostasis HSP70 function ↓; proteotoxic stress ↑; cancer stem-cell survival ↓ Potential proteostasis toxicity (dose-dependent) R–G Apoptosis of bulk, stem-like and drug-resistant cancer populations HSP70 has been proposed as a direct functional target, providing a potential mechanism against chemoresistant subpopulations.
10 Autophagy LC3-II and autophagosome formation ↑ Insufficiently characterized G Context-dependent cell death or survival adaptation Autophagy may contribute to cytotoxicity in some models but protect tumor cells in others; combination with autophagy inhibition can enhance activity experimentally.
11 EMT invasion and angiogenesis EMT ↓; MMP-2 and MMP-9 ↓; VEGF ↓; migration and invasion ↓ Endothelial angiogenic activity may ↓ G Reduced metastatic and angiogenic phenotype Primarily preclinical and often secondary to suppression of NF-κB, STAT3, AKT or β-catenin signalling.
12 MUC1-C PD-L1 immune-evasion axis MUC1-C ↓; PD-L1 ↓; CD8-positive T-cell activity ↑ in immunocompetent models Normal immune effects uncertain G Reduced immune evasion Promising but model-specific evidence; no clinical immunotherapy combination data are available.
13 Chemosensitization Resistance signalling ↓; apoptosis with gemcitabine, erlotinib or other agents ↑ Combination toxicity uncertain G Enhanced experimental treatment response Combination effects remain preclinical and cannot currently support adjunct use in patients.
14 Clinical Translation Constraint Systemic exposure after oral dosing very low Hepatic and cardiac injury possible; CYP-mediated interactions possible G Limits clinical feasibility and therapeutic index Poor solubility, approximately 0.1% rat oral bioavailability, extensive metabolism, uncertain human dosing, hepatotoxicity and cardiotoxicity prevent direct translation of micromolar in-vitro findings.

P: 0–30 min    R: 30 min–3 hr    G: >3 hr
COX2/PTGS2, cycloocygenase-2 (Cox-2) mRNA and Cox-2 protein: Click to Expand ⟱
Source: HalifaxProj(inhibit)
Type:
Cyclooxygenase-2 (COX-2) is an enzyme that plays a critical role in the conversion of arachidonic acid to prostaglandins, which are lipid compounds involved in various physiological processes, including inflammation, pain, and fever. COX-2 is an inducible enzyme, meaning its expression is typically low in normal tissues but can be upregulated in response to inflammatory stimuli, growth factors, and certain oncogenic signals.
-Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin biosynthesis, plays a key role in inflammation and circulatory homeostasis.
-COX-2 is an inducible enzyme that is upregulated in response to pro-inflammatory signals, including cytokines (e.g., IL-1β, TNF-α) and growth factors.

COX-2 is often overexpressed in various tumors, including colorectal, breast, lung, and prostate cancers.
The prostaglandins produced by COX-2, particularly prostaglandin E2 (PGE2), have several effects that can facilitate cancer progression:
Cell Proliferation: PGE2 can promote the proliferation of cancer cells by activating signaling pathways such as the PI3K/Akt and MAPK pathways.
Nonselective NSAIDs, such as aspirin and ibuprofen, inhibit both COX-1 and COX-2. Epidemiological studies have suggested that regular use of NSAIDs may reduce the risk of certain cancers, particularly colorectal cancer.
Drugs specifically targeting COX-2, such as celecoxib, have been developed.

COX-2 and xanthine oxidase are ROS-producing pro-oxidant enzymes that contribute to inflammation. Elevated COX‑2 levels, often found in inflammatory conditions or certain types of cancers, can contribute to increased production of ROS.
Scientific Papers found: Click to Expand⟱
1057- EVO,    Evodiamine abolishes constitutive and inducible NF-kappaB activation by inhibiting IkappaBalpha kinase activation, thereby suppressing NF-kappaB-regulated antiapoptotic and metastatic gene expression, up-regulating apoptosis, and inhibiting invasion
NF-kB↓, TNF-α↓, COX2/PTGS2↓, cycD1/CCND1↓, cMyc↓, MMP9↓, ICAM-1↓, MDR1↓, XIAP↓, Bcl-2↓, Bcl-xL↓, IAP1↓, IAP2/BIRC3↓, cFLIP↓, Bfl-1↓,

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:


Mitochondria & Bioenergetics(tgid=3) ⓘ

Bfl-1↓, 1,   XIAP↓, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

cMyc↓, 1,  

Cell Death(tgid=5) ⓘ

Bcl-2↓, 1,   Bcl-xL↓, 1,   cFLIP↓, 1,   IAP1↓, 1,   IAP2/BIRC3↓, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

cycD1/CCND1↓, 1,  

Migration(tgid=13) ⓘ

MMP9↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

COX2/PTGS2↓, 1,   ICAM-1↓, 1,   NF-kB↓, 1,   TNF-α↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

MDR1↓, 1,  
Total Targets: 15

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: COX2/PTGS2, cycloocygenase-2 (Cox-2) mRNA and Cox-2 protein
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#:76  Target#:66  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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