condition found tbRes List
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 bioA (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 on acheive 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. Given low bioavailability seems unlikely one could acheieve levels in vivo to raise ROS(except 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↓, 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↓, OXPHOS↓, GRP78↑, 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


HDAC, Histone deacetylases: Click to Expand ⟱
Source:
Type:
Enzymes involved in regulating gene expression by removing acetyl groups from histones, the proteins around which DNA is wrapped.
-Many cancers exhibit altered expression levels of HDACs, which can contribute to the dysregulation of genes involved in cell growth, survival, and differentiation.
-HDACs can repress the expression of tumor suppressor genes, leading to uncontrolled cell proliferation and survival. This repression can be a key factor in the development and progression of cancer.
-HDAC inhibitors (HDACi) have been developed and are being investigated for their ability to reactivate silenced genes, induce cell cycle arrest, and promote apoptosis in cancer cells.
-HDAC1, HDAC2): Often overexpressed in various cancers, including breast, prostate, and colorectal cancers. Their overexpression is associated with poor prognosis.
-HDAC4, HDAC5): These may have both oncogenic and tumor-suppressive roles depending on the context and cancer type.
-While HDACs are not classified as traditional oncogenes, their overexpression and activity can contribute to oncogenic processes.
-HDAC inhibitor works by preventing the removal of acetyl groups from histones, thereby modulating gene expression, influencing cell behavior, and potentially reversing aberrant gene silencing seen in various diseases.
-HDAC inhibitors can help reactivate these genes, thereby inhibiting growth and inducing apoptosis in cancer cells.
Scientific Papers found: Click to Expand⟱
3322- SIL,    Therapeutic intervention of silymarin on the migration of non-small cell lung cancer cells is associated with the axis of multiple molecular targets including class 1 HDACs, ZEB1 expression, and restoration of miR-203 and E-cadherin expression
- in-vitro, Lung, A549 - in-vitro, Lung, H1299 - in-vitro, Lung, H460
HDAC↓, associated with the inhibition of histone deacetylase (HDAC) activity and reduced levels of class 1 HDAC proteins (HDAC1, HDAC2, HDAC3 and HDAC8
HDAC1↓,
HDAC2↓,
HDAC3↓,
HDAC8↓,
HATs↑, and concomitant increases in the levels of histone acetyltransferase activity (HAT).
Zeb1↓, Treatment of A549 and H460 cells with silymarin reduced the expression of the transcription factor ZEB1 and restored expression of E-cadherin.
E-cadherin↑,
TumCMig↓, These findings indicate that silymarin can effectively inhibit lung cancer cell migration

3282- SIL,    Role of Silymarin in Cancer Treatment: Facts, Hypotheses, and Questions
- Review, NA, 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↓,
*NA↓, 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

3288- SIL,    Silymarin in cancer therapy: Mechanisms of action, protective roles in chemotherapy-induced toxicity, and nanoformulations
- Review, Var, NA
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↓,
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


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 3

Results for Effect on Cancer/Diseased Cells:
Akt↓,1,   angioG↓,2,   AntiCan↑,1,   APAF1↑,1,   AR↓,1,   ATP↓,1,   BAX↑,1,   Bcl-2↓,1,   Bcl-xL↓,1,   BIM↓,1,   BioAv↓,3,   CA↓,1,   Ca+2↑,1,   cardioP↑,2,   Casp↑,2,   Casp3↑,1,   CD31↓,1,   CD44↓,1,   CDK4↓,1,   chemoP↑,2,   cMyc↓,1,   COX2↓,1,   cycD1↓,1,   Cyt‑c↑,2,   Dose↝,1,   E-cadherin↑,2,   eff↝,1,   EGFR↓,1,   EMT↓,2,   ERK↓,2,   FAK↓,1,   GSH↑,1,   Half-Life↓,1,   Half-Life↝,1,   HATs↑,3,   HDAC↓,3,   HDAC1↓,1,   HDAC2↓,1,   HDAC3↓,1,   HDAC8↓,1,   hepatoP↑,2,   Hif1a↓,2,   IFN-γ↑,1,   IGFBP3↑,1,   IL1↓,1,   IL10↓,1,   IL2↑,1,   Inflam↓,1,   LC3II↑,1,   lipid-P↓,1,   MAPK↓,1,   MDSCs↓,1,   MEK↓,1,   miR-203↑,1,   MMP↓,2,   MMP2↓,1,   MMP9↓,1,   MMPs↓,1,   mTOR↓,1,   neuroP↑,1,   NF-kB↓,1,   NHE1↓,1,   NOTCH↓,1,   P21↑,1,   p27↑,1,   P53↑,1,   PCNA↓,1,   PD-L1↓,1,   PDGF↓,1,   PGE2↓,1,   PI3K↓,1,   PSA↓,1,   Raf↓,1,   ROS↓,1,   selectivity↑,1,   SIRT1↓,1,   SREBP1↓,1,   STAT3↓,1,   survivin↓,1,   Telomerase↓,1,   TGF-β↓,1,   toxicity↝,1,   toxicity∅,1,   TumCCA↑,1,   TumCG↓,1,   TumCMig↓,2,   TumMeta↓,1,   uPA↓,2,   VEGF↓,3,   VEGFR2↓,1,   Vim↓,1,   Wnt↓,1,   YAP/TEAD↓,1,   Zeb1↓,2,   β-catenin/ZEB1↓,1,  
Total Targets: 95

Results for Effect on Normal Cells:
antiOx↑,1,   BioAv↓,1,   IL8↓,1,   Inflam↓,1,   NA↓,1,   SIRT1↑,1,   TIMP1↓,1,  
Total Targets: 7

Scientific Paper Hit Count for: HDAC, Histone deacetylases
3 Silymarin (Milk Thistle) silibinin
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:154  Target#:140  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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