Natural Product (NP) Details

General Information of the NP (ID: NP0016)
Name
Silibinin
Synonyms
Silybin; 22888-70-6; Flavobin; Silymarin I; Silybin A; Silybine; Silibinine; Silliver; Silibinin A; Silibininum; Silibinina; Flavobin Spofa; Silymarine I; Silibinin [INN]; Silymarine; Silibininum [INN-Latin]; Silibinine [INN-French]; Silibinina [INN-Spanish]; 7C3MT; UNII-33X338MNE4; EINECS 245-302-5; NSC 651520; Silimarin; Silibin; CHEBI:9144; 33X338MNE4; Silibinin (INN); NSC651520; C25H22O10; NCGC00091057-01; DSSTox_CID_6018; DSSTox_RID_77985; DSSTox_GSID_26018; (2R,3R)-3,5,7-trihydroxy-2-((2R,3R)-3-(4-hydroxy-
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Species Origin Carduus marianus ...     Click to Show/Hide
Carduus marianus
Kingdom: Viridiplantae
Phylum: Streptophyta
Class: Magnoliopsida
Order: Asterales
Family: Asteraceae
Genus: Silybum
Species: Carduus marianus
Disease Hepatic encephalopathy [ICD-11: DB99] Phase 2/3 [1]
Structure
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2D MOL

3D MOL

ADMET Property
Absporption
Caco-2 Permeability
 -6.37
 
MDCK Permeability
 -5.164
 
PAMPA
 - -
 
HIA
 - - -
 
Distribution
VDss
 0.119
 
PPB
 95.1%
 
BBB
 - - -
 
Metabolism
CYP1A2 inhibitor
 - - -
CYP1A2 substrate
 ++
CYP2C19 inhibitor
 - - -
CYP2C19 substrate
 - - -
CYP2C9 inhibitor
 - - -
CYP2C9 substrate
 - -
CYP2D6 inhibitor
 - - -
CYP2D6 substrate
 - -
CYP3A4 inhibitor
 ++
CYP3A4 substrate
 -
CYP2B6 inhibitor
 - -
CYP2B6 substrate
 - - -
CYP2C8 inhibitor
 ++
HLM Stability
 - - -
 
Excretion
CLplasma
 5.633
 
T1/2
 2.476
Toxicity
DILI
 +++
 
Rat Oral Acute Toxicity
 -
 
FDAMDD
 - -
 
Respiratory
 -
 
Human Hepatotoxicity
 +++
 
Ototoxicity
 +
 
Drug-induced Nephrotoxicity
 +++
 
Drug-induced Neurotoxicity
 +
 
Hematotoxicity
 -
 
Genotoxicity
 +++
 
Tips: 1. For the classification endpoints, the prediction probability values are transformed into six symbols: 0-0.1 (- - -), 0.1-0.3 (- -), 0.3-0.5 (-), 0.5-0.7 (+), 0.7-0.9 (++), and 0.9-1.0 (+++). 2. Additionally, the corresponding relationships of the three labels are as follows: excellent; medium; poor.
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    Click to Show/Hide the Molecular Information and External Link(s) of This Natural Product
Formula
C25H22O10
PubChem CID
31553
Canonical SMILES
COC1=C(C=CC(=C1)C2C(OC3=C(O2)C=C(C=C3)C4C(C(=O)C5=C(C=C(C=C5O4)O)O)O)CO)O
InChI
1S/C25H22O10/c1-32-17-6-11(2-4-14(17)28)24-20(10-26)33-16-5-3-12(7-18(16)34-24)25-23(31)22(30)21-15(29)8-13(27)9-19(21)35-25/h2-9,20,23-29,31H,10H2,1H3/t20-,23+,24-,25-/m1/s1
InChIKey
SEBFKMXJBCUCAI-HKTJVKLFSA-N
CAS Number
CAS 22888-70-6
ChEBI ID
CHEBI:9144
Herb ID
HBIN044028
TTD Drug ID
D02ADM
Combinatorial Therapeutic Effect(s) Validated Clinically or Experimentally
    α. A List of Drug(s) Whose Efficacy can be Enhanced by This NP
          Regorafenib      Colorectal cancer     Click to Show/Hide the Molecular Data of This Drug
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [2]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation EIF4EBP1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation S6K1  Molecule Info 
Pathway MAP
                    In-vitro Model SW48 CVCL_1724 Colon adenocarcinoma Homo sapiens
GEO CVCL_0271 Colon carcinoma Homo sapiens
LIM1215 CVCL_2574 Colon adenocarcinoma Homo sapiens
HCT 15 CVCL_0292 Colon adenocarcinoma Homo sapiens
HCT 116 CVCL_0291 Colon carcinoma Homo sapiens
SW480 CVCL_0546 Colon adenocarcinoma Homo sapiens
LoVo CVCL_0399 Colon adenocarcinoma Homo sapiens
SW620 CVCL_0547 Colon adenocarcinoma Homo sapiens
                    Experimental
                    Result(s)		 The combined treatment with regorafenib and silybin induced synergistic anti-proliferative and apoptotic effects by blocking PI3K/AKT/mTOR intracellular pathway.
          TNF-related apoptosis inducing ligand      Lung cancer     Click to Show/Hide the Molecular Data of This Drug
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [3]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Down-regulation Expression BIRC3  Molecule Info 
Pathway MAP
Up-regulation Expression PSG1  Molecule Info 
Pathway MAP
Up-regulation Expression TRAIL-R2  Molecule Info 
Pathway MAP
                    Biological
                    Regulation		 Up-regulation ROS generation
                    In-vitro Model A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
NCI-H460 CVCL_0459 Lung large cell carcinoma Homo sapiens
                    Experimental
                    Result(s)		 Silibinin sensitizes TRAIL-mediated apoptosis by upregulating DR5 through ROS-induced endoplasmic reticulum stress-Ca 2+-CaMKII-Sp1 pathway.
          Vorinostat      Mycosis fungoides     Click to Show/Hide the Molecular Data of This Drug
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [4]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-xL  Molecule Info 
Pathway MAP
Down-regulation Expression BIRC5  Molecule Info 
Pathway MAP
Down-regulation Expression CCNB1  Molecule Info 
Pathway MAP
Up-regulation Expression CDKN1A  Molecule Info 
Pathway MAP
Down-regulation Expression MCL1  Molecule Info 
Pathway MAP
Down-regulation Expression POLD1  Molecule Info 
Pathway MAP
Down-regulation Expression XIAP  Molecule Info 
Pathway MAP
                    Biological
                    Regulation		 Induction Cell cycle arrest in G2/M phase
                    In-vitro Model NCI-H1299 CVCL_0060 Lung large cell carcinoma Homo sapiens
NCI-H358 CVCL_1559 Lung adenocarcinoma Homo sapiens
NCI-H322 CVCL_1556 Lung adenocarcinoma Homo sapiens
                    In-vivo Model Six week old athymic (nu/nu) male nude mice were subcutaneously injected with three million exponentially growing H1299 cells mixed with equal volume (1:1) of matrigel on the right flank of each mouse.
                    Experimental
                    Result(s)		 Combinations of SAHA with silibinin synergistically augmented the cytotoxic effects of the single agent, which was associated with a dramatic increase in p21 (Cdkn1a).
          Sorafenib      Renal cell carcinoma     Click to Show/Hide the Molecular Data of This Drug
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [5]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Down-regulation Expression KLF4  Molecule Info 
Pathway MAP
Down-regulation Expression MCL1  Molecule Info 
Pathway MAP
Down-regulation Expression NANOG  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation STAT3  Molecule Info 
Pathway MAP
                    In-vitro Model SMMC-7721 CVCL_0534 Hepatocellular carcinoma Homo sapiens
BEL-7402 CVCL_5492 Human hepatocellular carcinoma Homo sapiens
BEL-7404 CVCL_6568 Human hepatocellular carcinoma Homo sapiens
Hep-G2 CVCL_0027 Hepatocellular carcinoma Homo sapiens
MHCC97-H CVCL_4972 Adult hepatocellular carcinoma Homo sapiens
MHCC97-L CVCL_4973 Adult hepatocellular carcinoma Homo sapiens
HCCLM3 CVCL_6832 Adult hepatocellular carcinoma Homo sapiens
Hepa 1-6 CVCL_0327 Hepatocellular carcinoma of the mouse Mus musculus
H22 CVCL_H613 Hepatocellular carcinoma of the mouse Mus musculus
                    In-vivo Model Athymic nude mice or male C57BL/6 mice (aged 4-6 weeks and weighing 16-18g) were injected with Bel-7404 cells or Hepa 1-6 cells subcutaneously in the right foreleg (4*106 cells/mouse).
                    Experimental
                    Result(s)		 Combined treatment with sorafenib and silibinin synergistically targets both HCC cells and cancer stem cells by enhanced inhibition of the phosphorylation of STAT3/ERK/AKT.
          Trichostatin A      Solid tumour/cancer     Click to Show/Hide the Molecular Data of This Drug
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [4]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-xL  Molecule Info 
Pathway MAP
Down-regulation Expression BIRC5  Molecule Info 
Pathway MAP
Down-regulation Expression CCNB1  Molecule Info 
Pathway MAP
Up-regulation Expression CDKN1A  Molecule Info 
Pathway MAP
Down-regulation Expression MCL1  Molecule Info 
Pathway MAP
Down-regulation Expression POLD1  Molecule Info 
Pathway MAP
Down-regulation Expression XIAP  Molecule Info 
Pathway MAP
                    Biological
                    Regulation		 Induction Cell cycle arrest in G2/M phase
                    In-vitro Model NCI-H1299 CVCL_0060 Lung large cell carcinoma Homo sapiens
NCI-H358 CVCL_1559 Lung adenocarcinoma Homo sapiens
NCI-H322 CVCL_1556 Lung adenocarcinoma Homo sapiens
                    In-vivo Model Six week old athymic (nu/nu) male nude mice were subcutaneously injected with about three million exponentially growing H1299 cells mixed with equal volume (1:1) of matrigel on the right flank of each mouse.
                    Experimental
                    Result(s)		 Combinations of TSA with silibinin synergistically augmented the cytotoxic effects of the single agent, which was associated with a dramatic increase in p21 (Cdkn1a).
          IPI-549      Solid tumour/cancer     Click to Show/Hide the Molecular Data of This Drug
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [6]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Biological
                    Regulation		 Down-regulation Regulatory T cells and myeloid suppressor cells
                    In-vivo Model 4T1 cells was inoculated subcutaneously into the right mammary glands of female balb/c mice.
                    Experimental
                    Result(s)		 Tumor-targeted delivery of silibinin and IPI-549 synergistically inhibit breast cancer by remodeling the microenvironment.
          Methotrexate      Leukaemia     Click to Show/Hide the Molecular Data of This Drug
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [7]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vitro Model Human rhabdomyosarcoma Rhabdomyosarcoma Homo sapiens
                    Experimental
                    Result(s)		 Silibinin improves the cytotoxicity of methotrexate in chemo resistant human rhabdomyosarcoma cell lines.
          Dicyclohexylcarbodiimide      Prostate cancer     Click to Show/Hide the Molecular Data of This Drug
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [8]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vitro Model Enterococcus faecium Microorganism model Enterococcus faecium
Escherichia coli Microorganism model Escherichia coli
Pseudomonas aeruginosa Microorganism model Pseudomonas aeruginosa
                    Experimental
                    Result(s)		 Silybin showed a remarkable synergistic activity in combination with some antibiotic agents against drug-resistant bacteria.
          Mitoxantrone      Solid tumour/cancer     Click to Show/Hide the Molecular Data of This Drug
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [9]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vitro Model DU145 CVCL_0105 Prostate carcinoma Homo sapiens
LNCaP CVCL_0395 Prostate carcinoma Homo sapiens
PC-3 CVCL_0035 Prostate carcinoma Homo sapiens
                    Experimental
                    Result(s)		 The combination of silibinin and mitoxantrone exhibits a pattern of synergy in reducing cell viability with increased apoptosis.
    β. A List of Drug(s) Whose Adverse Effect can be Decreased by This NP
          Indole-3-carbinol      Breast cancer     Click to Show/Hide the Molecular Data of This Drug
                 Decreasing Adverse Drug Reaction     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [10]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Down-regulation Expression CCND1  Molecule Info 
Pathway MAP
Down-regulation Expression CDK2  Molecule Info 
Pathway MAP
Down-regulation Expression CDK4  Molecule Info 
Pathway MAP
Down-regulation Expression COX-2  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation NFKBIA  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation RB1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation STAT3  Molecule Info 
Pathway MAP
                    In-vitro Model Bronchial 1799 and 1198 cells Healthy Homo sapiens
                    Experimental
                    Result(s)		 Combinations of indole-3-carbinol and silibinin suppress inflammation-driven mouse lung tumorigenesis by modulating critical cell cycle regulators.
          Cisplatin      Bladder cancer     Click to Show/Hide the Molecular Data of This Drug
                 Decreasing Adverse Drug Reaction     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [11]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vitro Model L-02 CVCL_6926 Ovarian cancer Homo sapiens
A2780 CVCL_0134 Ovarian endometrioid adenocarcinoma Homo sapiens
                    Experimental
                    Result(s)		 silibinin could restore the sensitivity of cisplatin in drug-resistant human ovarian cancer cells and reduce durg-induced hepatotoxicity in cell level.
    γ. A List of Drug(s) Whose Resistance can be Reversed by This NP
          1,25-dihydroxyvitamin D3      Congenital alopecia     Click to Show/Hide the Molecular Data of This Drug
                 Reversing Drug Resistance     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [12]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression SNAI1  Molecule Info 
Pathway MAP
Down-regulation Expression SNAI2  Molecule Info 
Pathway MAP
Up-regulation Expression VDR  Molecule Info 
Pathway MAP
                    In-vitro Model HT-29 CVCL_0320 Colon adenocarcinoma Homo sapiens
SW480R CVCL_AT68 Colon adenocarcinoma Homo sapiens
                    Experimental
                    Result(s)		 Silibinin restored 1,25D responsiveness in vitamin D-resistant colon cancer cells by downregulation of Snail1 and Snail2 and upregulation of vitamin D receptor.
          Erlotinib      Lung cancer     Click to Show/Hide the Molecular Data of This Drug
                 Reversing Drug Resistance     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [13]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Down-regulation Expression EGFR  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation ERK1  Molecule Info 
Pathway MAP
                    In-vitro Model A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
NCI-H460 CVCL_0459 Lung large cell carcinoma Homo sapiens
NCI-H1299 CVCL_0060 Lung large cell carcinoma Homo sapiens
NCI-H1975 CVCL_1511 Lung adenocarcinoma Homo sapiens
HCC827 CVCL_2063 Lung adenocarcinoma Homo sapiens
LK2 CVCL_W132 Ovarian carcinoma Homo sapiens
PC-9 CVCL_B260 Lung adenocarcinoma Homo sapiens
293T GNE CVCL_0V13 Healthy Homo sapiens
                    In-vivo Model Tumors were grown by implanting 5*106 cells in Matrigel into female SCID mice flanks.
                    Experimental
                    Result(s)		 Combined treatment with silibinin and epidermal growth factor receptor tyrosine kinase inhibitors overcomes drug resistance caused by T790M mutation.
          Gefitinib      Lung cancer     Click to Show/Hide the Molecular Data of This Drug
                 Reversing Drug Resistance     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [13]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Down-regulation Expression EGFR  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation ERK1  Molecule Info 
Pathway MAP
                    In-vitro Model A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
NCI-H460 CVCL_0459 Lung large cell carcinoma Homo sapiens
NCI-H1299 CVCL_0060 Lung large cell carcinoma Homo sapiens
NCI-H1975 CVCL_1511 Lung adenocarcinoma Homo sapiens
HCC827 CVCL_2063 Lung adenocarcinoma Homo sapiens
LK2 CVCL_W132 Ovarian carcinoma Homo sapiens
PC-9 CVCL_B260 Lung adenocarcinoma Homo sapiens
293T GNE CVCL_0V13 Healthy Homo sapiens
                    In-vivo Model Animal models were constructed by implanting 5*106 PC-9 cells in Matrigel into the flanks of female severe combined immunodeficiency (SCID) mice.
                    Experimental
                    Result(s)		 Combined treatment with silibinin and epidermal growth factor receptor tyrosine kinase inhibitors overcomes drug resistance caused by T790M mutation.
          Doxorubicin      Solid tumour/cancer     Click to Show/Hide the Molecular Data of This Drug
                 Reversing Drug Resistance     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [14]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression SLC2A1  Molecule Info 
Pathway MAP
                    In-vitro Model LoVo CVCL_0399 Colon adenocarcinoma Homo sapiens
                    Experimental
                    Result(s)		 Silybin counteracts doxorubicin resistance by inhibiting GLUT1 expression.
References
Reference 1 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
Reference 2 Regorafenib in combination with silybin as a novel potential strategy for the treatment of metastatic colorectal cancer. Oncotarget. 2017 Aug 7;8(40):68305-68316.
Reference 3 Silibinin sensitizes TRAIL-mediated apoptosis by upregulating DR5 through ROS-induced endoplasmic reticulum stress-Ca 2+-CaMKII-Sp1 pathway. Oncotarget. 2017 Dec 7;9(12):10324-10342.
Reference 4 Epigenetic modifications and p21-cyclin B1 nexus in anticancer effect of histone deacetylase inhibitors in combination with silibinin on non-small cell lung cancer cells. Epigenetics. 2012 Oct;7(10):1161-72.
Reference 5 Combined treatment with sorafenib and silibinin synergistically targets both HCC cells and cancer stem cells by enhanced inhibition of the phosphorylation of STAT3/ERK/AKT. Eur J Pharmacol. 2018 Aug 5;832:39-49.
Reference 6 Tumor-targeted delivery of silibinin and IPI-549 synergistically inhibit breast cancer by remodeling the microenvironment. Int J Pharm. 2020 May 15;581:119239.
Reference 7 Silibinin improves the cytotoxicity of methotrexate in chemo resistant human rhabdomyosarcoma cell lines. Saudi Med J. 2013 Nov;34(11):1145-50.
Reference 8 Synergistic antibacterial effect between silybin and N,N'-dicyclohexylcarbodiimide in clinical Pseudomonas aeruginosa isolates. J Microbiol. 2008 Aug;46(4):462-7.
Reference 9 Silibinin synergizes with mitoxantrone to inhibit cell growth and induce apoptosis in human prostate cancer cells. Int J Cancer. 2007 May 1;120(9):2028-33.
Reference 10 Combinations of indole-3-carbinol and silibinin suppress inflammation-driven mouse lung tumorigenesis by modulating critical cell cycle regulators. Carcinogenesis. 2015 Jun;36(6):666-75.
Reference 11 Silibinin restores the sensitivity of cisplatin and taxol in A2780-resistant cell and reduces drug-induced hepatotoxicity. Cancer Manag Res. 2019 Jul 26;11:7111-7122.
Reference 12 Restoration of the anti-proliferative and anti-migratory effects of 1,25-dihydroxyvitamin D by silibinin in vitamin D-resistant colon cancer cells. Cancer Lett. 2015 Jul 1;362(2):199-207.
Reference 13 Combined treatment with silibinin and epidermal growth factor receptor tyrosine kinase inhibitors overcomes drug resistance caused by T790M mutation. Mol Cancer Ther. 2010 Dec;9(12):3233-43.
Reference 14 Silybin counteracts doxorubicin resistance by inhibiting GLUT1 expression. Fitoterapia. 2018 Jan;124:42-48.
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