Silymarin (Milk Thistle) silibinin / Casp9 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↓, 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)
Casp9, Caspase-9: Click to Expand ⟱
Source:
Type:
Caspase-9 is the apoptotic initiator protease of the intrinsic or mitochondrial apoptotic pathway, which is activated at multi-protein activation platforms.
Caspases are divided into two groups: the initiator caspases (caspase-2, -8, -9 and -10), which are the first to be activated in response to a signal, and the executioner caspases (caspase-3, -6, and -7) that carry out the demolition phase of apoptosis.
Caspase-9:
Role: Initiator caspase in the intrinsic apoptotic pathway.
Cancers: Frequently studied in leukemia and solid tumors.
Prognosis: Reduced expression is often linked to chemoresistance and poor prognosis.
Scientific Papers found: Click to Expand⟱
3325- SIL,    Modulatory effect of silymarin on pulmonary vascular dysfunction through HIF-1α-iNOS following rat lung ischemia-reperfusion injury
- in-vivo, Nor, NA
*Inflam↓, *ROS↓, *Casp3↑, *Casp9↑, *Hif1a↓, *iNOS↓, *SOD↑, *MDA↓,
3648- SIL,    Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years
- Review, NA, NA
*antiOx↑, *Inflam↓, *lipid-P↓, *necrosis↓, *hepatoP↑, *IL1↓, *IL6↓, *TNF-α↓, *IFN-γ↓, MAPK↓, Apoptosis↑, Cyt‑c↑, Casp3↑, Casp9↑, *PPARγ↑, *GLUT4↑, *HSPs↓, *HSP27↑, *Trx↑, *SIRT1↑, *ALAT↓, *GSH↑, *lipid-P↓, *TNF-α↓, TumCG↓, P21↑, CDK4↑,
3293- SIL,    Silymarin (milk thistle extract) as a therapeutic agent in gastrointestinal cancer
- Review, Var, NA
hepatoP↑, TumMeta↓, Inflam↓, chemoP↑, radioP↑, Half-Life↝, *GSTs↑, p‑JNK↑, BAX↑, p‑p38↑, cl‑PARP↑, Bcl-2↓, p‑ERK↓, TumVol↓, eff↑, TumCCA↑, STAT3↓, Mcl-1↓, survivin↓, Bcl-xL↓, Casp3↑, Casp9↑, eff↑, CXCR4↓, Dose↝,
3289- SIL,    Silymarin: a promising modulator of apoptosis and survival signaling in cancer
- Review, Var, NA
*BioAv↝, *BioAv↓, Fas↑, FasL↑, FADD↑, pro‑Casp8↑, Apoptosis↑, DR5↑, Bcl-2↑, BAX↑, Casp3↑, PI3K↓, FOXM1↓, p‑mTOR↓, p‑P70S6K↓, Hif1a↓, Akt↑, angioG↓, STAT3↓, NF-kB↓, lipid-P↓, eff↑, CDK1↓, survivin↓, CycB/CCNB1↓, Mcl-1↓, Casp9↑, AP-1↓, BioAv↑,
978- SIL,    A comprehensive evaluation of the therapeutic potential of silibinin: a ray of hope in cancer treatment
- Review, NA, NA
PI3K↓, Akt↓, NF-kB↓, Wnt/(β-catenin)↓, MAPK↓, TumCP↓, TumCCA↑, Apoptosis↑, p‑EGFR↓, JAK2↓, STAT5↓, cycD1/CCND1↓, hTERT/TERT↓, AP-1↓, MMP9↓, miR-21↓, miR-155↓, Casp9↑, BID↑, ERK↓, Akt2↓, DNMT1↓, P53↑, survivin↓, Casp3↑, ROS↑,
1140- SIL,    Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth
- in-vitro, PC, AsPC-1 - in-vivo, PC, NA - in-vitro, PC, MIA PaCa-2 - in-vitro, PC, PANC1 - in-vitro, PC, Bxpc-3
TumCG↓, Glycolysis↓, cMyc↓, STAT3↓, TumCP↓, Weight∅, Strength↑, DNAdam↑, Casp3↑, Casp9↑, GLUT1↓, HK2↓, LDHA↓, GlucoseCon↓, lactateProd↓, PPP↓, Ki-67↓, p‑STAT3↓, cachexia↓,
3305- SIL,    Silymarin inhibits proliferation of human breast cancer cells via regulation of the MAPK signaling pathway and induction of apoptosis
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, MCF-7 - in-vivo, NA, NA
TumCP↓, tumCV↓, BAX↑, cl‑PARP↑, Casp9↑, p‑JNK↑, Bcl-2↓, p‑p38↓, p‑ERK↓, *toxicity∅, Dose↝, *hepatoP↑, Inflam↓, AntiCan↑,
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↓,

Showing Research Papers: 1 to 8 of 8

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 8

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

lipid-P↓, 1,   ROS↑, 2,  

Core Metabolism/Glycolysis ⓘ

cMyc↓, 2,   GlucoseCon↓, 1,   Glycolysis↓, 1,   HK2↓, 1,   lactateProd↓, 1,   LDHA↓, 1,   PPP↓, 1,  

Cell Death ⓘ

Akt↓, 1,   Akt↑, 1,   Apoptosis↓, 1,   Apoptosis↑, 3,   BAX↑, 3,   Bcl-2↓, 3,   Bcl-2↑, 1,   Bcl-xL↓, 2,   BID↑, 1,   Casp3↑, 6,   pro‑Casp8↑, 1,   Casp9↑, 7,   Cyt‑c↑, 1,   DR5↑, 1,   FADD↑, 1,   Fas↑, 1,   FasL↑, 1,   hTERT/TERT↓, 1,   p‑JNK↓, 1,   p‑JNK↑, 2,   MAPK↓, 2,   Mcl-1↓, 3,   p‑p38↓, 2,   p‑p38↑, 1,   survivin↓, 4,  

Kinase & Signal Transduction ⓘ

HER2/EBBR2↓, 1,  

Transcription & Epigenetics ⓘ

miR-21↓, 1,   tumCV↓, 1,  

DNA Damage & Repair ⓘ

DNAdam↑, 1,   DNMT1↓, 1,   P53↑, 2,   cl‑PARP↑, 2,   PCNA↓, 1,  

Cell Cycle & Senescence ⓘ

CDK1↓, 2,   CDK4↑, 1,   CycB/CCNB1↓, 2,   cycD1/CCND1↓, 2,   P21↑, 1,   TumCCA↑, 3,  

Proliferation, Differentiation & Cell State ⓘ

CSCs↓, 1,   EMT↓, 1,   ERK↓, 1,   p‑ERK↓, 3,   FOXM1↓, 1,   p‑mTOR↓, 1,   p‑P70S6K↓, 1,   PI3K↓, 2,   STAT3↓, 4,   p‑STAT3↓, 1,   STAT5↓, 1,   TumCG↓, 3,   Wnt↓, 1,   Wnt/(β-catenin)↓, 1,  

Migration ⓘ

Akt2↓, 1,   AP-1↓, 2,   E-cadherin↑, 1,   Ki-67↓, 1,   miR-155↓, 1,   MMP2↓, 1,   MMP9↓, 2,   N-cadherin↓, 1,   TGF-β↓, 1,   TumCP↓, 3,   TumMeta↓, 2,   Vim↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 2,   p‑EGFR↓, 1,   Hif1a↓, 2,   VEGF↓, 1,  

Barriers & Transport ⓘ

GLUT1↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   CXCR4↓, 2,   IL1β↓, 1,   IL6↓, 1,   Inflam↓, 3,   JAK2↓, 1,   NF-kB↓, 2,   PGE2↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↑, 1,   Dose↝, 2,   eff↑, 6,   Half-Life↝, 1,  

Clinical Biomarkers ⓘ

p‑EGFR↓, 1,   FOXM1↓, 1,   HER2/EBBR2↓, 1,   hTERT/TERT↓, 1,   IL6↓, 1,   Ki-67↓, 1,  

Functional Outcomes ⓘ

AntiCan↑, 1,   cachexia↓, 1,   chemoP↑, 2,   hepatoP↑, 1,   radioP↑, 2,   Strength↑, 1,   TumVol↓, 1,   Weight∅, 1,  
Total Targets: 105

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 1,   GSH↑, 1,   GSTs↑, 1,   lipid-P↓, 2,   MDA↓, 1,   ROS↓, 2,   SOD↑, 1,   Trx↑, 1,  

Core Metabolism/Glycolysis ⓘ

ALAT↓, 1,   PPARγ↑, 1,   SIRT1↑, 1,  

Cell Death ⓘ

Casp3↑, 1,   Casp9↑, 1,   iNOS↓, 1,   necrosis↓, 1,  

Protein Folding & ER Stress ⓘ

HSP27↑, 1,   HSPs↓, 1,  

Angiogenesis & Vasculature ⓘ

Hif1a↓, 1,  

Barriers & Transport ⓘ

GLUT4↑, 1,  

Immune & Inflammatory Signaling ⓘ

IFN-γ↓, 1,   IL1↓, 1,   IL6↓, 1,   Inflam↓, 2,   TNF-α↓, 2,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 1,   BioAv↝, 1,  

Clinical Biomarkers ⓘ

ALAT↓, 1,   IL6↓, 1,  

Functional Outcomes ⓘ

hepatoP↑, 2,   toxicity∅, 1,  
Total Targets: 30

Scientific Paper Hit Count for: Casp9, Caspase-9
8 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#:45  State#:%  Dir#:2
  wNotes=0  sortOrder:rid,rpid

 

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