Natural Product (NP) Details

General Information of the NP (ID: NP8751)
Name
Shikonin
Synonyms
NSC 252844; Shikonin S; Shikonin,(S); Tokyo Violet
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Species Origin Lithospermum erythrorhizon ...     Click to Show/Hide
Lithospermum erythrorhizon
Kingdom: Viridiplantae
Phylum: Streptophyta
Class: Magnoliopsida
Order: Boraginales
Family: Boraginaceae
Genus: Lithospermum
Species: Lithospermum erythrorhizon
Disease Zoonotic viral disease [ICD-11: 1D6Y] Investigative [1]
Structure
Click to Download Mol
2D MOL

3D MOL

ADMET Property
Absporption
Caco-2 Permeability
 -4.775
 
MDCK Permeability
 -4.637
 
PAMPA
 +++
 
HIA
 - - -
 
Distribution
VDss
 0.622
 
PPB
 84.3%
 
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
 13.043
 
T1/2
 1.859
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
C16H16O5
PubChem CID
479503
Canonical SMILES
CC(=CCC(C1=CC(=O)C2=C(C=CC(=C2C1=O)O)O)O)C
InChI
1S/C16H16O5/c1-8(2)3-4-10(17)9-7-13(20)14-11(18)5-6-12(19)15(14)16(9)21/h3,5-7,10,17-19H,4H2,1-2H3/t10-/m1/s1
InChIKey
NEZONWMXZKDMKF-SNVBAGLBSA-N
CAS Number
CAS 517-89-5
Herb ID
HBIN043899
ETMC ID
6222
SymMap ID
SMIT01617
TTD Drug ID
D0QM4U
Combinatorial Therapeutic Effect(s) Validated Clinically or Experimentally
    α. A List of Drug(s) Whose Efficacy can be Enhanced by This NP
          Cisplatin      Bladder 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		 Up-regulation Expression BAX  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Up-regulation Activity CASP3  Molecule Info 
Pathway MAP
Up-regulation Activity CASP9  Molecule Info 
Pathway MAP
                    Biological
                    Regulation		 Induction ROS generation
Induction Loss of mitochondrial membrane potential
                    In-vitro Model HCT 116 CVCL_0291 Colon carcinoma Homo sapiens
HT-29 CVCL_0320 Colon adenocarcinoma Homo sapiens
SW620 CVCL_0547 Colon adenocarcinoma Homo sapiens
NCM460 CVCL_0460 Healthy Homo sapiens
                    In-vivo Model HCT116 cells (5*106 cells in 100uL of PBS) were harvested and injected subcutaneously into the right flank of five-week-old athymic BALB/cA nu/nu female mice.
                    Experimental
                    Result(s)		 Shikonin as a synergistic agent to cisplatin could be a highly efficient way to achieve anticancer synergism by inducing intracellular oxidative stress.
          Temozolomide      Brain 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 AKT1  Molecule Info 
Pathway MAP
Down-regulation Expression MMP-2  Molecule Info 
Pathway MAP
Down-regulation Expression MMP-9  Molecule Info 
Pathway MAP
Down-regulation Expression SNAI2  Molecule Info 
Pathway MAP
Down-regulation Expression VIM  Molecule Info 
Pathway MAP
                    In-vitro Model U-118MG CVCL_0633 Glioma Homo sapiens
                    Experimental
                    Result(s)		 GBM-derived cells treated with a combination of SHK and TMZ showed decreases in their proliferation and migration capacities. These decreases were followed by the suppression of GMT through a reduction of beta3 integrin, MMP-2, MMP-9, Slug and vimentin expression via inactivation of PI3K/AKT signaling.
          4-hydroxy-tamoxifen      Cyclic Mastalgia     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 [4]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression BID  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP8  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP9  Molecule Info 
Pathway MAP
Up-regulation Expression FAS  Molecule Info 
Pathway MAP
Down-regulation Expression PIK3CB  Molecule Info 
Pathway MAP
                    Biological
                    Regulation		 Down-regulation Loss of mitochondrial membrane potential
                    In-vitro Model MCF-7 CVCL_0031 Invasive breast carcinoma Homo sapiens
MDA-MB-435S CVCL_0622 Breast cancer Homo sapiens
                    In-vivo Model Portions of the suspension (6*106 MCF-7 cells in 0.1 mL) were subcutaneously injected into the right fanks of each female nude mice.
                    Experimental
                    Result(s)		 Shikonin and 4-hydroxytamoxifen synergistically inhibit the proliferation of breast cancer cells through activating apoptosis signaling pathway in vitro and in vivo.
          Erlotinib      Lung 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 [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 Phosphorylation EGFR  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation PLCG1  Molecule Info 
Pathway MAP
                    In-vitro Model U-87MG ATCC CVCL_0022 Glioblastoma Homo sapiens
DK-MG CVCL_1173 Glioblastoma Homo sapiens
SNB-19 CVCL_0535 Glioblastoma Homo sapiens
BS-153 CVCL_S444 Glioblastoma Homo sapiens
A-172 CVCL_0131 Glioblastoma Homo sapiens
T98G CVCL_0556 Glioblastoma Homo sapiens
U-251MG CVCL_0021 Astrocytoma Homo sapiens
                    Experimental
                    Result(s)		 Shikonin not only dose-dependently inhibited EGFR phosphorylation and decreased phosphorylation of EGFR downstream molecules, including AKT, P44/42MAPK and PLCgamma1, but also together with erlotinib synergistically inhibited deltaEGFR phosphorylation in U87MG.
          Gefitinib      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 [6]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression CCND1  Molecule Info 
Pathway MAP
Down-regulation Expression PKM  Molecule Info 
Pathway MAP
Down-regulation Expression STAT3  Molecule Info 
Pathway MAP
                    In-vitro Model A-549 CVCL_0023 Lung adenocarcinoma 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
                    In-vivo Model Animal models were constructed by injecting A549 cells (1*107) into nude mice (six-week) in the dorsal area.
                    Experimental
                    Result(s)		 Shikonin enhances sensitization of gefitinib against wild-type EGFR non-small cell lung cancer via inhibition PKM2/stat3/cyclinD1 signal pathway.
          Osimertinib      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 [7]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression ATF-4  Molecule Info 
Pathway MAP
Up-regulation Phosphorylation EIF2S1  Molecule Info 
Pathway MAP
                    Biological
                    Regulation		 Up-regulation ROS generation
                    In-vitro Model A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
NCI-H1299 CVCL_0060 Lung large cell carcinoma Homo sapiens
NCI-H460 CVCL_0459 Lung large cell carcinoma Homo sapiens
                    Experimental
                    Result(s)		 Shikonin increased the anticancer activity of AZD9291 in primary wtEGFR NSCLC cells through ROS-mediated ER stress.
          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 [8]
                    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 BCL-xL  Molecule Info 
Pathway MAP
Up-regulation Expression BID  Molecule Info 
Pathway MAP
Down-regulation Expression CASP3  Molecule Info 
Pathway MAP
Down-regulation Expression CASP8  Molecule Info 
Pathway MAP
Down-regulation Expression CFLAR  Molecule Info 
Pathway MAP
Up-regulation Phosphorylation JNK1  Molecule Info 
Pathway MAP
Down-regulation Expression MCL1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation STAT3  Molecule Info 
Pathway MAP
Down-regulation Expression XIAP  Molecule Info 
Pathway MAP
                    In-vitro Model A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
                    Experimental
                    Result(s)		 Shikonin sensitizes A549 cells to TRAIL-induced apoptosis through the JNK, STAT3 and AKT pathways.
          Doxorubicin      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 [9]
                    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 microRNA 19a  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation mTOR  Molecule Info 
Pathway MAP
Down-regulation Expression MYC  Molecule Info 
Pathway MAP
                    In-vitro Model Raji CVCL_0511 EBV-related Burkitt lymphoma Homo sapiens
Namalwa CVCL_0067 EBV-related Burkitt lymphoma Homo sapiens
                    In-vivo Model A mixture of 1*107 Namalwa cells and PBS was injected subcutaneously in the right oxter of each male non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice (4 weeks old).
                    Experimental
                    Result(s)		 Shikonin exerts antitumor activity in Burkitt's lymphoma by inhibiting C-MYC and PI3K/AKT/mTOR pathway and acts synergistically with doxorubicin.
          Gemcitabine      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 [10]
                    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
Up-regulation Activity CASP3  Molecule Info 
Pathway MAP
Up-regulation Activity CASP9  Molecule Info 
Pathway MAP
Down-regulation Expression CCND1  Molecule Info 
Pathway MAP
Down-regulation Expression COX-2  Molecule Info 
Pathway MAP
Down-regulation Expression MMP-9  Molecule Info 
Pathway MAP
Down-regulation Expression MYC  Molecule Info 
Pathway MAP
Down-regulation Activity p105  Molecule Info 
Pathway MAP
Down-regulation Expression VEGFA  Molecule Info 
Pathway MAP
Down-regulation Expression XIAP  Molecule Info 
Pathway MAP
                    In-vitro Model PANC-1 CVCL_0480 Pancreatic ductal adenocarcinoma Homo sapiens
BxPC-3 CVCL_0186 Pancreatic ductal adenocarcinoma Homo sapiens
AsPC-1 CVCL_0152 Pancreatic ductal adenocarcinoma Homo sapiens
                    In-vivo Model Tumors were established by subcutaneous injection of 5*106 BxPC-3 cells into the flanks of male nude BALB/c mice.
                    Experimental
                    Result(s)		 Shikonin can suppress the growth of human pancreatic tumors and potentiate the antitumor effects of gemcitabine through the suppression of NF-kappaB and NF-kappaB-regulated gene products.
          Dimethylaminoparthenolide      Lung 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 [11]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Biological
                    Regulation		 Alteration Cellular metabolism
                    In-vitro Model Kasumi-2 CVCL_0590 B acute lymphoblastic leukemia Homo sapiens
KOPN-8 CVCL_1866 B acute lymphoblastic leukemia Homo sapiens
NALM-6 CVCL_0092 Adult B acute lymphoblastic leukemia Homo sapiens
RCH-ACV CVCL_1851 B acute lymphoblastic leukemia Homo sapiens
Reh CVCL_1650 B acute lymphoblastic leukemia Homo sapiens
                    Experimental
                    Result(s)		 Combination of dimethylaminoparthenolide and shikonin alters metabolism and inhibits proliferation of pediatric precursor-B cell acute lymphoblastic leukemia.
Target and Pathway
Target(s) COVID-19 papain-like proteinase (PL-PRO)  Molecule Info  [1]
References
Reference 1 Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature. 2020 Apr 9.
Reference 2 Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo. Biochem Biophys Res Commun. 2016 Jan 22;469(4):1075-82.
Reference 3 Dual treatment with shikonin and temozolomide reduces glioblastoma tumor growth, migration and glial-to-mesenchymal transition. Cell Oncol (Dordr). 2017 Jun;40(3):247-261.
Reference 4 Shikonin and 4-hydroxytamoxifen synergistically inhibit the proliferation of breast cancer cells through activating apoptosis signaling pathway in vitro and in vivo. Chin Med. 2020 Mar 10;15:23.
Reference 5 Shikonin and its derivatives inhibit the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with erlotinib. Int J Cancer. 2015 Sep 15;137(6):1446-56.
Reference 6 Shikonin enhances sensitization of gefitinib against wild-type EGFR non-small cell lung cancer via inhibition PKM2/stat3/cyclinD1 signal pathway. Life Sci. 2018 Jul 1;204:71-77.
Reference 7 A natural anthraquinone derivative shikonin synergizes with AZD9291 against wtEGFR NSCLC cells through reactive oxygen species-mediated endoplasmic reticulum stress. Phytomedicine. 2020 Mar;68:153189.
Reference 8 Shikonin sensitizes A549 cells to TRAIL-induced apoptosis through the JNK, STAT3 and AKT pathways. BMC Cell Biol. 2018 Dec 29;19(1):29.
Reference 9 Shikonin exerts antitumor activity in Burkitt's lymphoma by inhibiting C-MYC and PI3K/AKT/mTOR pathway and acts synergistically with doxorubicin. Sci Rep. 2018 Feb 20;8(1):3317.
Reference 10 Shikonin suppresses tumor growth and synergizes with gemcitabine in a pancreatic cancer xenograft model: Involvement of NF-kappaB signaling pathway. Biochem Pharmacol. 2014 Apr 1;88(3):322-33.
Reference 11 Identification of a synergistic combination of dimethylaminoparthenolide and shikonin alters metabolism and inhibits proliferation of pediatric precursor-B cell acute lymphoblastic leukemia. Mol Carcinog. 2020 Apr;59(4):399-411.
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