Database Query Results : Silymarin (Milk Thistle) silibinin, , Hif1a

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,

rainbow trout

*NO↓, SMN lowered the H/R-elevated NO, MDA and carbonylated protein levels, while it enhanced the TAC level.
*MDA↓,
*TAC↑,
*Hif1a↓, SMN regulated the H/R up-regulated level of HIF-1α and iNOS in examined tissues.
*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,

injected testosterone (3 mg/kg/day, subcutaneously (s.c.)) for 2 weeks.

Rats

*NF-kB↓, SIL attenuated testosterone-induced nuclear factor-kappa B (NF-κB), cyclooxygenase-II (COX-II), and inducible nitric oxide synthase (iNOS) upregulation
*Hif1a↓, Testosterone-induced downregulation of phosphatase and tensin homolog (PTEN) and upregulation of hypoxia-inducible factor 1α (HIF-1α) were alleviated by SIL.
*PTEN↑,
*Weight↓, Concomitant administration of SIL (50 mg/kg) significantly decreased the prostate weight and prostate index induced by testosterone by 0.64-fold and 0.68-fold, respectively
*NO↓, co-treatment with SIL significantly ameliorated testosterone-induced rise in NO
*IL6↓, SIL-treated group significantly down- regulated mRNA expression of IL-6 and IL-8 compared to testosterone-treated group
*IL8↓,
*COX2↓, SIL suppressed NF-ÎºB, COX-II, and iNOS expressions as well as nitric oxide level in several experimental models
*iNOS↓,

3327-

SIL,

Effects of silymarin on HIF‑1α and MDR1 expression in HepG‑2 cells under hypoxia

in-vitro,

Liver,

HepG2

SM at 0, 10, 20, and 40 mg/L for 8 h

MDR1↓, while the MDR1 mRNA expression decreased in a concentration-dependent manner
Hif1a↓, Additionally, the HIF?1α and P?Gp protein expression levels of the 10, 20, and 40 mg/L SM treatment groups decreased in a concentration-dependent manner compared with the control group
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

58.46

in-vitro,

Liver,

Hep3B

75.13 umol/L

*hepatoP↑, Silymarin (SM) had been used as a traditional liver protective drug for decades
chemoPv↑, SM has chemopreventive and chemosensitizing effects on multiple cancers.
ChemoSen↑,
TumCP↓, SM reduced cellular proliferation, migration, invasion, and colony formation, but induced apoptosis in HepG2 and Hep3B cells under hypoxia conditions.
TumCMig↓,
TumCI↓,
Hif1a↓, The inhibitory effect of SM on HepG2 and Hep3B cells under hypoxia is partially via downregulating HIF-1α/VEGF signaling
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,

Rats

*Inflam↓, Following silymarin treatment, inflammation and oxidative stress in the lung I/R-injury rats were demonstrably suppressed.
*ROS↓,
*Casp3↑, Treatment with silymarin also inhibited the activation of caspase-3 and −9, and hypoxia inducible factor-1α (HIF-1α) and inducible nitric oxide synthase (iNOS) protein expression in the lung I/R-injury rats.
*Casp9↑,
*Hif1a↓,
*iNOS↓,
*SOD↑, Silymarin increases SOD and reduces MDA levels in rat lungs following I/R injury
*MDA↓,

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,

hepatoP↑, well as hepatoprotective agents.
chemoP↑, silymarin could be beneficial to oncology patients, especially for the treatment of the side effects of anticancer chemotherapeutics.
*lipid-P↓, Silymarin has been shown to significantly reduce lipid peroxidation and exhibit anti-oxidant, antihypertensive, antidiabetic, and hepatoprotective effects
*antiOx↑,
tumCV↓, reduces the viability, adhesion, and migration of tumor cells by induction of apoptosis and formation of reactive oxygen species (ROS), reducing glutathione levels, B-cell lymphoma 2 (Bcl-2), survivin, cyclin D1, Notch 1 intracellular domain (NICD),
TumCMig↓,
Apoptosis↑,
ROS↑,
GSH↓,
Bcl-2↓,
survivin↓,
cycD1/CCND1↓,
NOTCH1↓,
BAX↑, as well as enhancing the amount of Bcl-2-associated X protein (Bax) level (
NF-kB↓, The suppression of NK-κB-regulated gene products (e.g., cyclooxygenase-2 (COX-2), lipoxygenase (LOX), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF), and interleukin-1 (IL-1)) mediates the anti-inflammatory effect of silymarin
COX2↓,
LOX1↓,
iNOS↓,
TNF-α↓,
IL1↓,
Inflam↓,
*toxicity↓, Silymarin is also safe for humans, hence at therapeutic doses patients demonstrated no negative effects at the high dose of 700 mg, three times a day, for 24 weeks
CXCR4↓, fig 2
EGFR↓,
ERK↓,
MMP↓, reduction in mitochondrial transmembrane potential due to an increase in cytosolic cytochrome complex (Cyt c) levels.
Cyt‑c↑,
TumCCA↑, Moreover, silymarin increased the percentage of cells in the gap 0/gap 1 (G0/G1) phase and decreased the percentage of cells in the synthesis (S)-phase,
RB1↑, concomitant up-regulation of retinoblastoma protein (Rb), p53, cyclin-dependent kinase inhibitor 1 (p21Cip1), and cyclin-dependent kinase inhibitor 1B (p27Kip1)
P53↑,
P21↑,
p27↑,
cycE/CCNE↓, and down-regulation of cyclin D1, cyclin E, cyclin-dependent kinase 4 (CDK4), and phospho-Rb
CDK4↓,
p‑pRB↓,
Hif1a↓, silibinin inhibited proliferation of Hep3B cells due to simultaneous induction of apoptosis and prevented the accumulation
cMyc↓, Silibinin also reduces cellular myelocytomatosis oncogene (c-MYC) expression, a key regulator of cancer metabolism in pancreatic cancer cells
IL1β↓, Silymarin can also inhibit the production of inflammatory cytokines, such as interleukin-1beta (IL-1β), interferon-gamma (IFNγ),
IFN-γ↓,
PCNA↓, ilymarin suppresses the high proliferative activity of cells started with a carcinogen so that it significantly inhibits proliferating cell nuclear antigen (PCNA) and cyclin D1 labeling indices
PSA↓, In another patent, S. marianum has been used as an estrogen receptor β-agonist and an inhibitor of PSA for treating prostate cancer
CYP1A1↓, Silymarin prevents the expression of CYP1A1 and COX-2

3289-

SIL,

Silymarin: a promising modulator of apoptosis and survival signaling in cancer

Review,

Var,

*BioAv↝, silymarin’s poor bioavailability and limited thérapeutic efficacy have been overcome by encapsulation of silymarin into nanoparticles
*BioAv↓, Silymarin is barely 20–50% absorbed by the GIT cells and has an absolute oral bioavailability of 0.95%
Fas↑, silibinin, enhances the Fas pathway in most cancers cells by upregulating the Fas and Fas L
FasL↑,
FADD↑, silymarin triggered apoptosis via upregulating the expression of FADD (Fig. 2b), a downstream component of the death receptor pathway, subsequently leading to the cleavage of procaspase 8 and initiation of apoptotic cell death
pro‑Casp8↑,
Apoptosis↑,
DR5↑, silymarin promotes apoptosis through the death receptor-mediated pathway, contributing to its anticancer effects
Bcl-2↑, Bcl-2, an anti-apoptotic protein, was decreased
BAX↑, Bax is also upregulated and leads to the activation of caspase-3.
Casp3↑,
PI3K↓, Silibinin inhibits the PI3K activity, leading to the reduction of FoxM1 (Forkhead box M1) and the subsequent activation of the mitochondrial apoptotic pathway
FOXM1↓,
p‑mTOR↓, inhibiting phosphorylation of several key components in this pathway, such as mTOR, p70S6K and 4E-BP1
p‑P70S6K↓,
Hif1a↓, mTOR pathway signaling in turn may result in low levels of HIF-1α due to the unfavorable conditions of hypoxia.
Akt↑, silibinin activates the Akt pathway in cervical cancer cells. This activation of Akt could have some bearing on the overall antitumor activity of silibinin in cervical cancer cells.
angioG↓, silibinin inhibited STAT3, HIF-1α, and NF-κB, thereby reducing the population of lung macrophages and limiting angiogenesis
STAT3↓,
NF-kB↓,
lipid-P↓, silibinin delays the progression of endometrial carcinoma via inhibiting STAT3 activation and lowering lipid accumulation, which is regulated by SREBP1
eff↑, Sorafenib and silibinin work together to target both liver cancer cells and cancer stem cells. This combination operates by suppressing the STAT3/ERK/AKT pathways and decreasing the production of Mcl-1 and Bcl-2 proteins
CDK1↓, reducing the expression of CDK1, survivin, Bcl-xL, cyclinB1 and Mcl- 1 and simultaneously activate caspases 3 and 9
survivin↓,
CycB/CCNB1↓,
Mcl-1↓,
Casp9↑,
AP-1↓, hindered the activation of transcription factors NF-κB and AP-1
BioAv↑, Liang et al., created a chitosan-based lipid polymer hybrid nanoparticles that boosted the bioavailability of silymarin by 14.38-fold

3288-

SIL,

Silymarin in cancer therapy: Mechanisms of action, protective roles in chemotherapy-induced toxicity, and nanoformulations

Review,

Var,

Inflam↓, Silymarin, a milk thistle extract, has anti-inflammatory, immunomodulatory, anti-lipid peroxidative, anti-fibrotic, anti-oxidative, and anti-proliferative properties.
lipid-P↓,
TumMeta↓, Silymarin exhibits not only anti-cancer functions through modulating various hallmarks of cancer, including cell cycle, metastasis, angiogenesis, apoptosis, and autophagy, by targeting a plethora of molecules
angioG↓,
chemoP↑, but also plays protective roles against chemotherapy-induced toxicity, such as nephrotoxicity,
EMT↓, Figure 2, Metastasis
HDAC↓,
HATs↑,
MMPs↓,
uPA↓,
PI3K↓,
Akt↓,
VEGF↓, Angiogenesis
CD31↓,
Hif1a↓,
VEGFR2↓,
Raf↓,
MEK↓,
ERK↓,
BIM↓, apoptosis
BAX↑,
Bcl-2↓,
Bcl-xL↓,
Casp↑,
MAPK↓,
P53↑,
LC3II↑, Autophagy
mTOR↓,
YAP/TEAD↓,
*BioAv↓, Additionally, the oral bioavailability of silymarin in rats is only 0.73 %
MMP↓, silymarin treatment reduced mitochondrial transmembrane potential, leading to an increase in cytosolic cytochrome c (Cyt c), downregulating proliferation-associated proteins (PCNA, c-Myc, cyclin D1, and β-catenin)
Cyt‑c↑,
PCNA↓,
cMyc↓,
cycD1/CCND1↓,
β-catenin/ZEB1↓,
survivin↓, and anti-apoptotic proteins (survivin and Bcl-2), and upregulating pro-apoptotic proteins (caspase-3, Bax, APAF-1, and p53)
APAF1↑,
Casp3↑,
MDSCs↓, ↓MDSCs, ↓IL-10, ↑IL-2 and IFN-γ
IL10↓,
IL2↑,
IFN-γ↑,
hepatoP↑, Moreover, in a randomized clinical trial, silymarin attenuated hepatoxicity in non-metastatic breast cancer patients undergoing a doxorubicin/cyclophosphamide-paclitaxel regimen
cardioP↑, For example, Rašković et al. studied the hepatoprotective and cardioprotective effects of silymarin (60 mg/kg orally) in rats following DOX
GSH↑, silymarin could protect the kidney and heart from ADR toxicity by protecting against glutathione (GSH) depletion and inhibiting lipid peroxidation
neuroP↑, silymarin attenuated the neurotoxicity of docetaxel by reducing apoptosis, inflammation, and oxidative stress

3282-

SIL,

Role of Silymarin in Cancer Treatment: Facts, Hypotheses, and Questions

Review,

NA,

hepatoP↑, This group of flavonoids has been extensively studied and they have been used as hepato-protective substances
AntiCan↑, however, silymarin compounds have clear anticancer effects
TumCMig↓, decreasing migration through multiple targeting, decreasing hypoxia inducible factor-1α expression, i
Hif1a↓, In prostate cancer cells silibinin inhibited HIF-1α translation
selectivity↑, antitumoral activity of silymarin compounds is limited to malignant cells while the nonmalignant cells seem not to be affected
toxicity∅, long history of silymarin use in human diseases without toxicity after prolonged administration.
*antiOx↑, as an antioxidant, by scavenging prooxidant free radicals
*Inflam↓, antiinflammatory effects similar to those of indomethacin,
TumCCA↑, MDA-MB 486 breast cancer cells, G1 arrest was found due to increased p21 and decreased CDKs activity
P21↑,
CDK4↓,
NF-kB↓, human prostate carcinoma cells, silymarin decreased ligand binding to Erb1 135 and NF-kB expression was strongly inhibited by silymarin in hepatoma cell
ERK↓, human prostate carcinoma cells, silymarin decreased ligand binding to Erb1 135 and NF-kB expression was strongly inhibited by silymarin in hepatoma cell
PSA↓, Treating prostate carcinoma cells with silymarin the levels of PSA were significantly decreased and cell growth was inhibited through decreased CDK activity and induction of Cip1/p21 and Kip1/p27. 1
TumCG↓,
p27↑,
COX2↓, such as anti-COX2 and anti-IL-1α activity, 140 antiangiogenic effects through inhibition of VEGF secretion, upregulation of Insulin like Growth Factor Binding Protein 3 (IGFBP3), 141 and inhibition of androgen receptors.
IL1↓,
VEGF↓,
IGFBP3↑,
AR↓,
STAT3↓, downregulation of the STAT3 pathway which was seen in many cell models.
Telomerase↓, silymarin has the ability to decrease telomerase activity in prostate cancer cells
Cyt‑c↑, mitochondrial cytochrome C release-caspase activation.
Casp↑,
eff↝, Malignant p53 negative cells show only minimal apoptosis when treated with silymarin. Therefore, one conclusion is that silymarin may be useful in tumors with conserved p53.
HDAC↓, inhibit histone deacetylase activity;
HATs↑, increase histone acetyltransferase activity
Zeb1↓, reduce expression of the transcription factor ZEB1
E-cadherin↑, increase expression of E-cadherin;
miR-203↑, increase expression of miR-203
NHE1↓, reduce activation of sodium hydrogen isoform 1 exchanger (NHE1)
MMP2↓, target β catenin and reduce the levels of MMP2 and MMP9
MMP9↓,
PGE2↓, reduce activation of prostaglandin E2
Vim↓, suppress vimentin expression
Wnt↓, inhibit Wnt signaling
angioG↓, Silymarin inhibits angiogenesis.
VEGF↓, VEGF downregulation
*TIMP1↓, Silymarin has the capacity to decrease TIMP1 expression166–168 in mice.
EMT↓, found that silibinin had no effect on EMT. However, the opposite was found in other malignant tissues160–162 where it showed inhibitory effects.
TGF-β↓, Silibinin reduces the expression of TGF β2 in different tumors such as triple negative breast, 174 prostate, and colorectal cancers.
CD44↓, Silibinin decreased CD44 expression and the activation of EGFR (epidermal growth factor receptor)
EGFR↓,
PDGF↓, silibinin had the ability to downregulate PDFG in fibroblasts, thus decreasing proliferation.
*IL8↓, Flavonoids, in general, reduce levels of IL-8. Curcumin, 200 apigenin, 201 and silybin showed the ability to decrease IL-8 levels
SREBP1↓, Silymarin inhibited STAT3 phosphorylation and decreased the expression of intranuclear sterol regulatory element binding protein 1 (SREBP1), decreasing lipid synthesis.
MMP↓, reduced membrane potential and ATP content
ATP↓,
uPA↓, silibinin decreased MMP2, MMP9, and urokinase plasminogen activator receptor level (uPAR) in neuroblastoma cells. uPAR is also a marker of cell invasion.
PD-L1↓, Silibinin inhibits PD-L1 by impeding STAT5 binding in NSCLC.
NOTCH↓, Silybin inhibited Notch signaling in hepatocellular carcinoma cells showing antitumoral effects
*SIRT1↑, Silymarin can also increase SIRT1 expression in other tissues, such as hippocampus, 221 articular chondrocytes, 222 and heart muscle
SIRT1↓, Silymarin seems to act differently in tumors: in lung cancer cells SIRT downregulated SIRT1 and exerted multiple antitumor effects such as reduced adhesion and migration and increased apoptosis.
CA↓, Silymarin has the ability to inhibit CA isoforms CA I and CA II.
Ca+2↑, ilymarin increases mitochondrial release of Ca++ and lowers mitochondrial membrane potential in cancer cell
chemoP↑, Silymarin: Decreasing Side Effects and Toxicity of Chemotherapeutic Drugs
cardioP↑, There is also evidence that it protects the heart from doxorubicin toxicity, however, it is less potent than quercetin in this effect.
Dose↝, oral administration of 240 mg of silybin to 6 healthy volunteers the following results were obtained 377 : maximum\,plasmaconcentration0.34±0.16⁢𝜇⁢g/m⁢L
Half-Life↝, and time to maximum plasma concentration 1.32 ± 0.45 h. Absorption half life 0.17 ± 0.09 h, elimination half life 6.32 ± 3.94 h
BioAv↓, silymarin is not soluble in water and oral administration shows poor absorption in the alimentary tract (approximately 1% in rats,
BioAv↓, Our conclusion is that, from a bioavailability standpoint, it is much easier to achieve migration inhibition, than proliferative reduction.
BioAv↓, Combination with succinate: is available on the market under the trade mark Legalon® (bis hemisuccinate silybin). Combination with phosphatidylcholine:
toxicity↝, 13 g daily per os divided into 3 doses was well tolerated. The most frequent adverse event was asymptomatic liver toxicity.
Half-Life↓, It may be necessary to administer 800 mg 4 times a day because the half-life is short.
ROS↓, its ability as an antioxidant reduces ROS production
FAK↓, Silibinin decreased human osteosarcoma cell invasion through Erk inhibition of a FAK/ERK/uPA/MMP2 pathway

1001-

SIL,

Silibinin down-regulates PD-L1 expression in nasopharyngeal carcinoma by interfering with tumor cell glycolytic metabolism

in-vitro,

NA,

0–200µM

100µM@72hr

 LMP-1+ NPC tumor cells (C666–1),

TumCG↓,
Glycolysis↓, Silibinin potently inhibits tumor growth and promotes a shift from aerobic glycolysis toward oxidative phosphorylation.
OXPHOS↑,
LDHA↓,
lactateProd↓,
i-citrate↑,
Hif1a↓,
PD-L1↓, silibinin can alter PD-L1 expression by interfering with HIF-1α/LDH-A

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

25,50uM

in-vitro,

Pca,

22Rv1

200 mg/kg

mice

TumCP↓,
Hif1a↓, strongly decreased hypoxia-induced HIF-1α expression
NADPH↓,
angioG↓,
FASN↓,
ACC↓,

3301-

SIL,

Critical review of therapeutic potential of silymarin in cancer: A bioactive polyphenolic flavonoid

Review,

Var,

Inflam↓, graphical abstract
TumCCA↑,
Apoptosis↓,
TumMeta↓,
TumCG↓,
angioG↓,
chemoP↑, The chemo-protective effects of silymarin and silibinin propose that they could be applied to decrease the side effects and increase the anti-tumor effects of chemotherapy and radiotherapy in different types of cancers.
radioP↑,
p‑ERK↓, fig 2
p‑p38↓,
p‑JNK↓,
P53↑,
Bcl-2↓,
Bcl-xL↓,
TGF-β↓,
MMP2↓,
MMP9↓,
E-cadherin↑,
Wnt↓,
Vim↓,
VEGF↓,
IL6↓,
STAT3↓,
*ROS↓,
IL1β↓,
PGE2↓,
CDK1↓, Causes cell cycle arrest by down-regulating CDK1, cyclinB1, survivin, Bcl-xl, Mcl-1 and activating caspase 3 and caspase 9,
CycB/CCNB1↓,
survivin↓,
Mcl-1↓,
Casp3↑,
Casp9↑,
cMyc↓, Silibinin treatment diminishes c-MYC
COX2↓, Silibinin considerably down-regulated the expression of COX-2, HIF-1α, VEGF, Ang-2, Ang-4, MMP-2, MMP-9, CCR-2 and CXCR-4
Hif1a↓,
CXCR4↓,
CSCs↓, HCT-116 cells, Induction of apoptosis, suppression of migration, elimination of CSCs. Attenuation of EMT via decreased expression of N- cadherin and vimentin and increased expression of (E-cadherin).
EMT↓,
N-cadherin↓,
PCNA↓, Decrease in PCNA and cyclin D1 level.
cycD1/CCND1↓,
ROS↑, Hepatocellular carcinoma: Silymarin nanoemulsion reduced the cell viability and increased ROS intensity and chromatin condensation.
eff↑, Silymarin + Curcumin
eff↑, Silibinin + Metformin
eff↑, Silibinin + 1, 25-vitamin D3
HER2/EBBR2↓, Significant down regulation of HER2 by 150 and 250 µM of silybin after 24, 48 and 72 h.

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

Pathway results for Effect on Cancer / Diseased Cells:

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#:%
  wNotes=on  sortOrder:rid,rpid

Database Query Results : Silymarin (Milk Thistle) silibinin, , Hif1a

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Kinase & Signal Transduction ⓘ

Transcription & Epigenetics ⓘ

Autophagy & Lysosomes ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Hormonal & Nuclear Receptors ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

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