Silymarin (Milk Thistle) silibinin / Hif1a 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)
Hif1a, HIF1α/HIF1a: Click to Expand ⟱
Source:
Type:
Hypoxia-Inducible-Factor 1A (HIF1A gene, HIF1α, HIF-1α protein product)
-Dominantly expressed under hypoxia(low oxygen levels) in solid tumor cells
-HIF1A induces the expression of vascular endothelial growth factor (VEGF)
-High HIF-1α expression is associated with Poor prognosis
-Low HIF-1α expression is associated with Better prognosis

-Functionally, HIF-1α is reported to regulate glycolysis, whilst HIF-2α regulates genes associated with lipoprotein metabolism.
-Cancer cells produce HIF in response to hypoxia in order to generate more VEGF that promote angiogenesis

Key mediators of aerobic glycolysis regulated by HIF-1α.
-GLUT-1 → regulation of the flux of glucose into cells.
-HK2 → catalysis of the first step of glucose metabolism.
-PKM2 → regulation of rate-limiting step of glycolysis.
-Phosphorylation of PDH complex by PDK → blockage of OXPHOS and promotion of aerobic glycolysis.
-LDH (LDHA): Rapid ATP production, conversion of pyruvate to lactate;

HIF-1α Inhibitors:
-Curcumin: disruption of signaling pathways that stabilize HIF-1α (ie downregulate).
-Resveratrol: downregulate HIF-1α protein accumulation under hypoxic conditions.
-EGCG: modulation of upstream signaling pathways, leading to decreased HIF-1α activity.
-Emodin: reduce HIF-1α expression. (under hypoxia).
-Apigenin: inhibit HIF-1α accumulation.
Scientific Papers found: Click to Expand⟱
3329- SIL,    Silymarin regulates the HIF-1 and iNOS expression in the brain and Gills of the hypoxic-reoxygenated rainbow trout (Oncorhynchus mykis)
- in-vivo, Nor, NA
*NO↓, *MDA↓, *TAC↑, *Hif1a↓, *iNOS↓,
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↓,
3327- SIL,    Effects of silymarin on HIF‑1α and MDR1 expression in HepG‑2 cells under hypoxia
- in-vitro, Liver, HepG2
MDR1↓, Hif1a↓, P-gp↓,
3326- SIL,    Silymarin suppresses proliferation of human hepatocellular carcinoma cells under hypoxia through downregulation of the HIF-1α/VEGF pathway
- in-vitro, Liver, HepG2 - in-vitro, Liver, Hep3B
*hepatoP↑, chemoPv↑, ChemoSen↑, TumCP↓, TumCMig↓, TumCI↓, Hif1a↓, VEGF↓, angioG↓,
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↓,
964- SIL,    Silibinin inhibits hypoxia-induced HIF-1α-mediated signaling, angiogenesis and lipogenesis in prostate cancer cells: In vitro evidence and in vivo functional imaging and metabolomics
- vitro+vivo, Pca, LNCaP - in-vitro, Pca, 22Rv1
TumCP↓, Hif1a↓, NADPH↓, angioG↓, FASN↓, ACC↓,
3288- SIL,    Silymarin in cancer therapy: Mechanisms of action, protective roles in chemotherapy-induced toxicity, and nanoformulations
- Review, Var, NA
Inflam↓, lipid-P↓, TumMeta↓, angioG↓, chemoP↑, EMT↓, HDAC↓, HATs↑, MMPs↓, uPA↓, PI3K↓, Akt↓, VEGF↓, CD31↓, Hif1a↓, VEGFR2↓, Raf↓, MEK↓, ERK↓, BIM↓, BAX↑, Bcl-2↓, Bcl-xL↓, Casp↑, MAPK↓, P53↑, LC3II↑, mTOR↓, YAP/TEAD↓, *BioAv↓, MMP↓, Cyt‑c↑, PCNA↓, cMyc↓, cycD1/CCND1↓, β-catenin/ZEB1↓, survivin↓, APAF1↑, Casp3↑, MDSCs↓, IL10↓, IL2↑, IFN-γ↑, hepatoP↑, cardioP↑, GSH↑, neuroP↑,
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↓,
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↑,
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↓,
1001- SIL,    Silibinin down-regulates PD-L1 expression in nasopharyngeal carcinoma by interfering with tumor cell glycolytic metabolism
- in-vitro, NA, NA
TumCG↓, Glycolysis↓, OXPHOS↑, LDHA↓, lactateProd↓, i-citrate↑, Hif1a↓, PD-L1↓,
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 12 of 12

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 12

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

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

Mitochondria & Bioenergetics ⓘ

ATP↓, 1,   MEK↓, 1,   MMP↓, 3,   Raf↓, 1,  

Core Metabolism/Glycolysis ⓘ

ACC↓, 1,   i-citrate↑, 1,   cMyc↓, 3,   FASN↓, 1,   Glycolysis↓, 1,   lactateProd↓, 1,   LDHA↓, 1,   NADPH↓, 1,   SIRT1↓, 1,   SREBP1↓, 1,  

Cell Death ⓘ

Akt↓, 1,   Akt↑, 1,   APAF1↑, 1,   Apoptosis↓, 1,   Apoptosis↑, 2,   BAX↑, 3,   Bcl-2↓, 3,   Bcl-2↑, 1,   Bcl-xL↓, 2,   BIM↓, 1,   Casp↑, 2,   Casp3↑, 3,   pro‑Casp8↑, 1,   Casp9↑, 2,   Cyt‑c↑, 3,   DR5↑, 1,   FADD↑, 1,   Fas↑, 1,   FasL↑, 1,   iNOS↓, 1,   p‑JNK↓, 1,   MAPK↓, 1,   Mcl-1↓, 2,   p27↑, 2,   p‑p38↓, 1,   survivin↓, 4,   Telomerase↓, 1,   YAP/TEAD↓, 1,  

Kinase & Signal Transduction ⓘ

HER2/EBBR2↓, 1,  

Transcription & Epigenetics ⓘ

HATs↑, 2,   p‑pRB↓, 1,   tumCV↓, 1,  

Autophagy & Lysosomes ⓘ

LC3II↑, 1,  

DNA Damage & Repair ⓘ

P53↑, 3,   PCNA↓, 3,  

Cell Cycle & Senescence ⓘ

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

Proliferation, Differentiation & Cell State ⓘ

CD44↓, 1,   CSCs↓, 1,   EMT↓, 3,   ERK↓, 3,   p‑ERK↓, 1,   FOXM1↓, 1,   HDAC↓, 2,   IGFBP3↑, 1,   mTOR↓, 1,   p‑mTOR↓, 1,   NOTCH↓, 1,   NOTCH1↓, 1,   p‑P70S6K↓, 1,   PI3K↓, 2,   STAT3↓, 3,   TumCG↓, 3,   Wnt↓, 2,  

Migration ⓘ

AP-1↓, 1,   CA↓, 1,   Ca+2↑, 1,   CD31↓, 1,   E-cadherin↑, 2,   FAK↓, 1,   miR-203↑, 1,   MMP2↓, 2,   MMP9↓, 2,   MMPs↓, 1,   N-cadherin↓, 1,   PDGF↓, 1,   TGF-β↓, 2,   TumCI↓, 1,   TumCMig↓, 3,   TumCP↓, 2,   TumMeta↓, 2,   uPA↓, 2,   Vim↓, 2,   Zeb1↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 6,   EGFR↓, 2,   Hif1a↓, 9,   LOX1↓, 1,   VEGF↓, 5,   VEGFR2↓, 1,  

Barriers & Transport ⓘ

NHE1↓, 1,   P-gp↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 3,   CXCR4↓, 2,   IFN-γ↓, 1,   IFN-γ↑, 1,   IL1↓, 2,   IL10↓, 1,   IL1β↓, 2,   IL2↑, 1,   IL6↓, 1,   Inflam↓, 3,   MDSCs↓, 1,   NF-kB↓, 3,   PD-L1↓, 2,   PGE2↓, 2,   PSA↓, 2,   TNF-α↓, 1,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 3,   BioAv↑, 1,   ChemoSen↑, 1,   Dose↝, 1,   eff↑, 4,   eff↝, 1,   Half-Life↓, 1,   Half-Life↝, 1,   MDR1↓, 1,   selectivity↑, 1,  

Clinical Biomarkers ⓘ

AR↓, 1,   EGFR↓, 2,   FOXM1↓, 1,   HER2/EBBR2↓, 1,   IL6↓, 1,   PD-L1↓, 2,   PSA↓, 2,  

Functional Outcomes ⓘ

AntiCan↑, 1,   cardioP↑, 2,   chemoP↑, 4,   chemoPv↑, 1,   hepatoP↑, 3,   neuroP↑, 1,   radioP↑, 1,   toxicity↝, 1,   toxicity∅, 1,  
Total Targets: 153

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 2,   lipid-P↓, 1,   MDA↓, 2,   ROS↓, 2,   SOD↑, 1,   TAC↑, 1,  

Core Metabolism/Glycolysis ⓘ

SIRT1↑, 1,  

Cell Death ⓘ

Casp3↑, 1,   Casp9↑, 1,   iNOS↓, 3,  

Proliferation, Differentiation & Cell State ⓘ

PTEN↑, 1,  

Migration ⓘ

TIMP1↓, 1,  

Angiogenesis & Vasculature ⓘ

Hif1a↓, 3,   NO↓, 2,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   IL6↓, 1,   IL8↓, 2,   Inflam↓, 2,   NF-kB↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 2,   BioAv↝, 1,  

Clinical Biomarkers ⓘ

IL6↓, 1,  

Functional Outcomes ⓘ

hepatoP↑, 1,   toxicity↓, 1,   Weight↓, 1,  
Total Targets: 25

Scientific Paper Hit Count for: Hif1a, HIF1α/HIF1a
12 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#:143  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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