Silymarin (Milk Thistle) silibinin / COX2 Cancer Research Results

SIL, Silymarin (Milk Thistle) silibinin: Click to Expand ⟱
Features:
Silymarin (Milk Thistle) Flowering herb related to daisy and ragweed family.
Silibinin (INN), also known as silybin is the major active constituent of silymarin, a standardized extract of the milk thistle seeds.
-a flavonoid combination of 65–80% of seven flavolignans; the most important of these include silybin, isosilybin, silychristin, isosilychristin, and silydianin. Silybin is the most abundant compound in around 50–70% in isoforms silybin A and silybin B

-Note half-life 6hrs?.
BioAv not soluble in water, low bioAv (1%). 240mg yielded only 0.34ug/ml plasma level. oral administration of SM (equivalent to 120 mg silibinin), total (unconjugated + conjugated) silibinin concentration in plasma was 1.1–1.3 μg/mL, so can not achieve levels used in most in-vitro studies.
Pathways:
- results for both inducing and reducing ROS in cancer cells. In normal cell seems to consistently lower ROS. Reports show both ROS↑ and ROS↓ in cancer models; systemic pro-oxidant effects may require higher exposures than typical oral dosing, but local or combination contexts may differ. (level in GUT could be much higher (800uM).
- ROS↑ related: MMP↓(ΔΨm), Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑,
- Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓">COX2↓, p38↓(context-dependent; often stress-activated), Pro-Inflammatory Cytokines : NLRP3↓, IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, TIMP2, uPA↓, VEGF↓, FAK↓, NF-κB↓, CXCR4↓, TGF-β↓, α-SMA↓, ERK↓
- reactivate genes thereby inhibiting cancer cell growth : HDAC↓, DNMTs↓, P53↑, HSP↓,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, TNF-α↓, FAK↓, ERK↓, EMT↓,
- inhibits glycolysis and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, GRP78↑(ER stress), Glucose↓, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, Notch↓, PDGF↓, EGFR↓,
- inhibits Cancer Stem Cells : CSC↓, Hh↓, GLi1↓, β-catenin↓, Notch2↓, OCT4↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK, ERK↓, JNK, - SREBP (related to cholesterol).
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,

- Selectivity: Cancer Cells vs Normal Cells

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 ROS / redox buffering + mitochondrial protection Often ↑ stress susceptibility; can support apoptosis when survival signaling is blocked ↓ oxidative stress; mitochondrial protection P, R, G Context-selective redox modulation Silymarin is classically cytoprotective/antioxidant in normal tissues (notably liver), while in tumors it can weaken pro-survival adaptation and increase vulnerability to stressors and therapy.
2 Intrinsic apoptosis (mitochondria → caspases) ↑ apoptosis signaling; ↑ caspase activation ↔ minimal activation G Cell death execution Common downstream outcome in cancer models: apoptosis increases after earlier signaling/redox shifts and/or checkpoint disruption.
3 Cell-cycle control (cyclins/CDKs; checkpoints) ↑ arrest (G1/S or G2/M depending on model) ↔ G Cytostasis Typically observed as reduced proliferation with checkpoint engagement; timing usually later than kinase phosphorylation changes.
4 NF-κB inflammatory transcription ↓ NF-κB activity; ↓ inflammatory/pro-survival tone ↔ or protective anti-inflammatory effect R, G Anti-inflammatory / anti-survival transcription NF-κB suppression can reduce tumor-promoting inflammation and blunt stress-adaptive survival programs.
5 JAK/STAT3 axis (incl. PD-L1 / immune escape programs in some models) ↓ STAT3 signaling (context); may ↓ PD-L1 in certain tumor contexts ↔ R, G Reduced survival + immune-evasion signaling Reported to attenuate STAT3-driven tumor programs and, in some contexts, reduce immune-suppressive signaling (model dependent).
6 PI3K → AKT → mTOR survival / growth signaling ↓ PI3K/AKT/mTOR signaling (context) ↔ R, G Growth/survival suppression Reduced PI3K/AKT/mTOR tone increases sensitivity to apoptosis and can reinforce cell-cycle arrest.
7 MAPK re-wiring (ERK/p38/JNK balance) Stress-MAPK shifts; ERK tone often reduced or re-patterned ↔ P, R, G Signal reprogramming Early phosphorylation shifts can precede later gene-expression changes; exact ERK direction is model and dose dependent.
8 Angiogenesis (VEGF and angiogenic factors) ↓ VEGF / angiogenesis outputs ↔ G Anti-angiogenic support Typically reflected in reduced pro-angiogenic expression/secretion and angiogenesis-related phenotypes over longer windows.
9 EMT / invasion / migration programs (incl. TGF-β/Smad-associated EMT in some systems) ↓ EMT markers; ↓ migration/invasion ↔ G Anti-invasive phenotype Often presents as restoration of epithelial markers and suppression of migration/invasion assays; commonly a later phenotype-level outcome.
10 Xenobiotic handling (Phase I/II enzymes; cytoprotection / chemoprevention framing) May alter carcinogen activation/detox balance ↑ detox / cytoprotection against xenobiotics G Chemopreventive protection A key “dual strategy” theme: protection of normal tissue from toxins/therapy while modulating tumor response pathways.
11 Drug resistance / efflux (MDR phenotype; P-gp-related resistance in some models) May ↓ functional MDR and ↑ chemo sensitivity (context) ↔ R, G Chemo-sensitization support Reported synergy with chemotherapy in resistant tumor settings; transporter direction can be context-specific, so present as “reported to reduce functional resistance” rather than a universal single-transporter claim.
12 Immune microenvironment signaling (cytokines / macrophage recruitment in some models) May ↓ pro-tumor cytokine programs and recruitment signals (context) ↔ G Anti-inflammatory tumor microenvironment shift Immune-modulatory effects are increasingly discussed, but they are more model-dependent and typically show on longer time scales.

Time-Scale Flag (TSF): P / R / G

  • P: 0–30 min (primary/physical–chemical effects; rapid signaling / phosphorylation shifts)
  • R: 30 min–3 hr (redox signaling + acute stress-response signaling)
  • G: >3 hr (gene-regulatory adaptation and phenotype-level outcomes)
COX2, 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⟱
3331- SIL,    The clinical anti-inflammatory effects and underlying mechanisms of silymarin
- Review, NA, NA
*Inflam↓, *NF-kB↓, *NLRP3↓, *COX2↓, *iNOS↓, *neuroP↑, *p‑ERK↓, *p38↓, *MAPK↓, *EGFR↓, *ROS↓, *lipid-P?, *5LO↓,
3330- SIL,    Mechanistic Insights into the Pharmacological Significance of Silymarin
- Review, Var, NA
*neuroP↑, *hepatoP↑, *cardioP↑, *antiOx↓, *NLRP3↓, *NAD↑, ROS↓, NLRP3↓, TumCMig↓, *COX2↓, *iNOS↓, *MPO↓, *AChE↓, *LDH↓, *Telomerase↓, *Fas↓,
3328- SIL,    Modulatory effect of silymarin on inflammatory mediators in experimentally induced benign prostatic hyperplasia: emphasis on PTEN, HIF-1α, and NF-κB
- in-vivo, BPH, NA
*NF-kB↓, *Hif1a↓, *PTEN↑, *Weight↓, *NO↓, *IL6↓, *IL8↓, *COX2↓, *iNOS↓,
3323- SIL,    Anticancer therapeutic potential of silibinin: current trends, scope and relevance
- Review, Var, NA
Inflam↓, angioG↓, antiOx↑, TumMeta↓, TumCP↓, TumCCA↑, TumCD↑, α-SMA↓, p‑Akt↓, p‑STAT3↓, COX2↓, IL6↓, MMP2↓, HIF-1↓, Snail↓, Slug↓, Zeb1↓, NF-kB↓, p‑EGFR↓, JAK2↓, PI3K↓, PD-L1↓, VEGF↓, CDK4↓, CDK2↓, cycD1/CCND1↓, E2Fs↓,
3320- SIL,    Neuroprotective Potential of Silymarin against CNS Disorders: Insight into the Pathways and Molecular Mechanisms of Action
- Review, AD, NA
*hepatoP↑, *neuroP↑, *ROS↓, *β-Amyloid↓, *Inflam↓, *Aβ↓, *NF-kB↓, *TNF-α↓, *TNF-β↓, *iNOS↓, *NO↓, *COX2↓,
3319- SIL,    Silymarin and neurodegenerative diseases: Therapeutic potential and basic molecular mechanisms
- Review, AD, NA - Review, Park, NA - Review, Stroke, NA
*neuroP↑, *ROS↓, *Inflam↓, *Apoptosis↓, *BBB?, *tau↓, *NF-kB↓, *IL1β↓, *TNF-α↓, *IL4↓, *MAPK↓, *memory↑, *cognitive↑, *Aβ↓, *ROS↓, *lipid-P↓, *GSH↑, *MDA↓, *SOD↑, *Catalase↑, *AChE↓, *BChE↓, *p‑ERK↓, *p‑JNK↓, *p‑p38↓, *GutMicro↑, *COX2↓, *iNOS↓, *TLR4↓, *neuroP↑, *Strength↑, *AMPK↑, *MMP↑, *necrosis↓, *NRF2↑, *HO-1↑,
3295- SIL,    Hepatoprotective effect of silymarin
- Review, NA, NA
*hepatoP↑, *ROS↓, *GSH↑, *BioAv↝, ERK↓, NF-kB↓, STAT3↓, COX2↓, Inflam↓, IronCh↑, lipid-P↓, ALAT↓, AST↓, TNF-α↓, *α-SMA↓, *SOD↑,
3290- SIL,    A review of therapeutic potentials of milk thistle (Silybum marianum L.) and its main constituent, silymarin, on cancer, and their related patents
- Analysis, Var, NA
hepatoP↑, chemoP↑, *lipid-P↓, *antiOx↑, tumCV↓, TumCMig↓, Apoptosis↑, ROS↑, GSH↓, Bcl-2↓, survivin↓, cycD1/CCND1↓, NOTCH1↓, BAX↑, NF-kB↓, COX2↓, LOX1↓, iNOS↓, TNF-α↓, IL1↓, Inflam↓, *toxicity↓, CXCR4↓, EGFR↓, ERK↓, MMP↓, Cyt‑c↑, TumCCA↑, RB1↑, P53↑, P21↑, p27↑, cycE/CCNE↓, CDK4↓, p‑pRB↓, Hif1a↓, cMyc↓, IL1β↓, IFN-γ↓, PCNA↓, PSA↓, CYP1A1↓,
3282- SIL,    Role of Silymarin in Cancer Treatment: Facts, Hypotheses, and Questions
- Review, NA, NA
hepatoP↑, AntiCan↑, TumCMig↓, Hif1a↓, selectivity↑, toxicity∅, *antiOx↑, *Inflam↓, TumCCA↑, P21↑, CDK4↓, NF-kB↓, ERK↓, PSA↓, TumCG↓, p27↑, COX2↓, IL1↓, VEGF↓, IGFBP3↑, AR↓, STAT3↓, Telomerase↓, Cyt‑c↑, Casp↑, eff↝, HDAC↓, HATs↑, Zeb1↓, E-cadherin↑, miR-203↑, NHE1↓, MMP2↓, MMP9↓, PGE2↓, Vim↓, Wnt↓, angioG↓, VEGF↓, *TIMP1↓, EMT↓, TGF-β↓, CD44↓, EGFR↓, PDGF↓, *IL8↓, SREBP1↓, MMP↓, ATP↓, uPA↓, PD-L1↓, NOTCH↓, *SIRT1↑, SIRT1↓, CA↓, Ca+2↑, chemoP↑, cardioP↑, Dose↝, Half-Life↝, BioAv↓, BioAv↓, BioAv↓, toxicity↝, Half-Life↓, ROS↓, FAK↓,
3301- SIL,    Critical review of therapeutic potential of silymarin in cancer: A bioactive polyphenolic flavonoid
- Review, Var, NA
Inflam↓, TumCCA↑, Apoptosis↓, TumMeta↓, TumCG↓, angioG↓, chemoP↑, radioP↑, p‑ERK↓, p‑p38↓, p‑JNK↓, P53↑, Bcl-2↓, Bcl-xL↓, TGF-β↓, MMP2↓, MMP9↓, E-cadherin↑, Wnt↓, Vim↓, VEGF↓, IL6↓, STAT3↓, *ROS↓, IL1β↓, PGE2↓, CDK1↓, CycB/CCNB1↓, survivin↓, Mcl-1↓, Casp3↑, Casp9↑, cMyc↓, COX2↓, Hif1a↓, CXCR4↓, CSCs↓, EMT↓, N-cadherin↓, PCNA↓, cycD1/CCND1↓, ROS↑, eff↑, eff↑, eff↑, HER2/EBBR2↓,
3300- SIL,    Toward the definition of the mechanism of action of silymarin: activities related to cellular protection from toxic damage induced by chemotherapy
- Review, Var, NA
*ROS↓, *SOD↑, *hepatoP↑, *AST↓, *ALAT↓, *lipid-P↓, *GSH↑, *Catalase↑, *GSTs↑, *GSR↑, *TNF-α↓, *IFN-γ↓, *IL4↓, *IL2↓, *NF-kB↓, *IL10↑, *Inflam↓, COX2↓, Apoptosis↑, ChemoSen↑, PGE2↓, VEGF↓,

Showing Research Papers: 1 to 11 of 11

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 11

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 1,   CYP1A1↓, 1,   GSH↓, 1,   lipid-P↓, 1,   ROS↓, 2,   ROS↑, 2,  

Metal & Cofactor Biology ⓘ

IronCh↑, 1,  

Mitochondria & Bioenergetics ⓘ

ATP↓, 1,   MMP↓, 2,  

Core Metabolism/Glycolysis ⓘ

ALAT↓, 1,   cMyc↓, 2,   SIRT1↓, 1,   SREBP1↓, 1,  

Cell Death ⓘ

p‑Akt↓, 1,   Apoptosis↓, 1,   Apoptosis↑, 2,   BAX↑, 1,   Bcl-2↓, 2,   Bcl-xL↓, 1,   Casp↑, 1,   Casp3↑, 1,   Casp9↑, 1,   Cyt‑c↑, 2,   iNOS↓, 1,   p‑JNK↓, 1,   Mcl-1↓, 1,   p27↑, 2,   p‑p38↓, 1,   survivin↓, 2,   Telomerase↓, 1,   TumCD↑, 1,  

Kinase & Signal Transduction ⓘ

HER2/EBBR2↓, 1,  

Transcription & Epigenetics ⓘ

HATs↑, 1,   p‑pRB↓, 1,   tumCV↓, 1,  

DNA Damage & Repair ⓘ

P53↑, 2,   PCNA↓, 2,  

Cell Cycle & Senescence ⓘ

CDK1↓, 1,   CDK2↓, 1,   CDK4↓, 3,   CycB/CCNB1↓, 1,   cycD1/CCND1↓, 3,   cycE/CCNE↓, 1,   E2Fs↓, 1,   P21↑, 2,   RB1↑, 1,   TumCCA↑, 4,  

Proliferation, Differentiation & Cell State ⓘ

CD44↓, 1,   CSCs↓, 1,   EMT↓, 2,   ERK↓, 3,   p‑ERK↓, 1,   HDAC↓, 1,   IGFBP3↑, 1,   NOTCH↓, 1,   NOTCH1↓, 1,   PI3K↓, 1,   STAT3↓, 3,   p‑STAT3↓, 1,   TumCG↓, 2,   Wnt↓, 2,  

Migration ⓘ

CA↓, 1,   Ca+2↑, 1,   E-cadherin↑, 2,   FAK↓, 1,   miR-203↑, 1,   MMP2↓, 3,   MMP9↓, 2,   N-cadherin↓, 1,   PDGF↓, 1,   Slug↓, 1,   Snail↓, 1,   TGF-β↓, 2,   TumCMig↓, 3,   TumCP↓, 1,   TumMeta↓, 2,   uPA↓, 1,   Vim↓, 2,   Zeb1↓, 2,   α-SMA↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 3,   EGFR↓, 2,   p‑EGFR↓, 1,   HIF-1↓, 1,   Hif1a↓, 3,   LOX1↓, 1,   VEGF↓, 5,  

Barriers & Transport ⓘ

NHE1↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 6,   CXCR4↓, 2,   IFN-γ↓, 1,   IL1↓, 2,   IL1β↓, 2,   IL6↓, 2,   Inflam↓, 4,   JAK2↓, 1,   NF-kB↓, 4,   PD-L1↓, 2,   PGE2↓, 3,   PSA↓, 2,   TNF-α↓, 2,  

Protein Aggregation ⓘ

NLRP3↓, 1,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 3,   ChemoSen↑, 1,   Dose↝, 1,   eff↑, 3,   eff↝, 1,   Half-Life↓, 1,   Half-Life↝, 1,   selectivity↑, 1,  

Clinical Biomarkers ⓘ

ALAT↓, 1,   AR↓, 1,   AST↓, 1,   EGFR↓, 2,   p‑EGFR↓, 1,   HER2/EBBR2↓, 1,   IL6↓, 2,   PD-L1↓, 2,   PSA↓, 2,  

Functional Outcomes ⓘ

AntiCan↑, 1,   cardioP↑, 1,   chemoP↑, 3,   hepatoP↑, 2,   radioP↑, 1,   toxicity↝, 1,   toxicity∅, 1,  
Total Targets: 127

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↓, 1,   antiOx↑, 2,   Catalase↑, 2,   GSH↑, 3,   GSR↑, 1,   GSTs↑, 1,   HO-1↑, 1,   lipid-P?, 1,   lipid-P↓, 3,   MDA↓, 1,   MPO↓, 1,   NRF2↑, 1,   ROS↓, 7,   SOD↑, 3,  

Mitochondria & Bioenergetics ⓘ

MMP↑, 1,  

Core Metabolism/Glycolysis ⓘ

ALAT↓, 1,   AMPK↑, 1,   LDH↓, 1,   NAD↑, 1,   SIRT1↑, 1,  

Cell Death ⓘ

Apoptosis↓, 1,   Fas↓, 1,   iNOS↓, 5,   p‑JNK↓, 1,   MAPK↓, 2,   necrosis↓, 1,   p38↓, 1,   p‑p38↓, 1,   Telomerase↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

p‑ERK↓, 2,   PTEN↑, 1,  

Migration ⓘ

5LO↓, 1,   TIMP1↓, 1,   α-SMA↓, 1,  

Angiogenesis & Vasculature ⓘ

EGFR↓, 1,   Hif1a↓, 1,   NO↓, 2,  

Barriers & Transport ⓘ

BBB?, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 5,   IFN-γ↓, 1,   IL10↑, 1,   IL1β↓, 1,   IL2↓, 1,   IL4↓, 2,   IL6↓, 1,   IL8↓, 2,   Inflam↓, 5,   NF-kB↓, 5,   TLR4↓, 1,   TNF-α↓, 3,   TNF-β↓, 1,  

Synaptic & Neurotransmission ⓘ

AChE↓, 2,   BChE↓, 1,   tau↓, 1,  

Protein Aggregation ⓘ

Aβ↓, 2,   NLRP3↓, 2,   β-Amyloid↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↝, 1,  

Clinical Biomarkers ⓘ

ALAT↓, 1,   AST↓, 1,   EGFR↓, 1,   GutMicro↑, 1,   IL6↓, 1,   LDH↓, 1,  

Functional Outcomes ⓘ

cardioP↑, 1,   cognitive↑, 1,   hepatoP↑, 4,   memory↑, 1,   neuroP↑, 5,   Strength↑, 1,   toxicity↓, 1,   Weight↓, 1,  
Total Targets: 72

Scientific Paper Hit Count for: COX2, cycloocygenase-2 (Cox-2) mRNA and Cox-2 protein
11 Silymarin (Milk Thistle) silibinin
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#:154  Target#:66  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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