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

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)
CSCs, Cancer Stem Cells: Click to Expand ⟱
Source:
Type:
Cancer Stem Cells

Phytochemicals (natural plant-derived compounds) that may affect CSCs:
Curcumin
— suppresses self-renewal and pathways (Wnt/Notch/Hedgehog).
Resveratrol
— shown to reduce CSC populations and sphere formation in multiple models.
Sulforaphane (from broccoli sprouts)
— reported to inhibit CSC properties and pathways; active in vitro and in vivo.
EGCG (epigallocatechin-3-gallate, green tea)
— reduces CSC markers and sphere formation in several cancer types.
Quercetin
— reported to inhibit CSC proliferation, self-renewal and invasiveness (breast, endometrial, others).
Berberine
— shown to suppress CSC “stemness” and reduce tumorigenic properties in multiple models.
Genistein (soy isoflavone)
— decreases CSC markers, sphere formation and stemness signaling in prostate/breast/other models.
Honokiol (Magnolia bark)
— shown to eliminate or suppress CSC-like populations in oral, colon, glioma models.
Luteolin
— inhibits stemness/EMT and reduces CSC markers and self-renewal in breast, prostate and other models.
Withaferin A (from Withania somnifera / ashwagandha)
— multiple preclinical reports show WA targets CSCs and reduces tumor growth/metastasis in models.

Circadian disruption in cancer and regulation of cancer stem cells by circadian clock genes: An updated review
Potential Role of the Circadian Clock in the Regulation of Cancer Stem Cells and Cancer Therapy
Can we utilise the circadian clock to target cancer stem cells?
Scientific Papers found: Click to Expand⟱
3301- SIL,    Critical review of therapeutic potential of silymarin in cancer: A bioactive polyphenolic flavonoid
- Review, Var, NA
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: 1

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

ROS↑, 1,  

Core Metabolism/Glycolysis ⓘ

cMyc↓, 1,  

Cell Death ⓘ

Apoptosis↓, 1,   Bcl-2↓, 1,   Bcl-xL↓, 1,   Casp3↑, 1,   Casp9↑, 1,   p‑JNK↓, 1,   Mcl-1↓, 1,   p‑p38↓, 1,   survivin↓, 1,  

Kinase & Signal Transduction ⓘ

HER2/EBBR2↓, 1,  

DNA Damage & Repair ⓘ

P53↑, 1,   PCNA↓, 1,  

Cell Cycle & Senescence ⓘ

CDK1↓, 1,   CycB/CCNB1↓, 1,   cycD1/CCND1↓, 1,   TumCCA↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

CSCs↓, 1,   EMT↓, 1,   p‑ERK↓, 1,   STAT3↓, 1,   TumCG↓, 1,   Wnt↓, 1,  

Migration ⓘ

E-cadherin↑, 1,   MMP2↓, 1,   MMP9↓, 1,   N-cadherin↓, 1,   TGF-β↓, 1,   TumMeta↓, 1,   Vim↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   Hif1a↓, 1,   VEGF↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   CXCR4↓, 1,   IL1β↓, 1,   IL6↓, 1,   Inflam↓, 1,   PGE2↓, 1,  

Drug Metabolism & Resistance ⓘ

eff↑, 3,  

Clinical Biomarkers ⓘ

HER2/EBBR2↓, 1,   IL6↓, 1,  

Functional Outcomes ⓘ

chemoP↑, 1,   radioP↑, 1,  
Total Targets: 45

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

ROS↓, 1,  
Total Targets: 1

Scientific Paper Hit Count for: CSCs, Cancer Stem Cells
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#:795  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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