condition found tbRes List
SK, Shikonin: Click to Expand ⟱
Features:
The (R)-enantiomer of alkannin is known as shikonin, and the racemic mixture of the two is known as shikalkin.
Shikonin is a naphthoquinone derivative primarily isolated from the roots of plants in the Boraginaceae family (e.g., Lithospermum erythrorhizon).
Shikonin is the main active component of a Chinese medicinal plant 'Zi Cao'
-Shikonin is a major component of zicao (purple gromwell, the dried root of Lithospermum erythrorhizon), a Chinese herbal medicine with anti-inflammatory properties
-Quinone methides (QMs) are highly reactive intermediates formed from natural compounds like shikonin
-ic50 cancer cells 1-10uM, normal cells >10uM

-known as Glycolysis inhibitor: ( inhibit pyruvate kinase M2 (PKM2*******), a key enzyme in the glycolytic pathway)

Available from mcsformulas.com Shikonin Pro Liposomal, 30 mg
Also In Glycolysis Inhibithree(100 mg PHLORIZIN,10 mg TANSHINONE IIA, 8 mg Shikonin)

-Note half-life15-30mins or 8hr?.
BioAv low, poor water solubility
Pathways:
- usually induce ROS production in cancer cells, and reduce ROS in normal cells.
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓,
- Lowers AntiOxidant defense in Cancer Cells: NRF2↓, TrxR↓**, SOD↓, GSH↓ Catalase↓ GPx4↓
- 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↓, IGF-1↓, uPA↓, VEGF↓, FAK↓, NF-κB↓, TGF-β↓, ERK↓
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, FAK↓, ERK↓, EMT↓,
- inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, ECAR↓, OXPHOS↓, GRP78↑, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓, Integrins↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, β-catenin↓, AMPK, ERK↓, JNK, P53↑,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,

- Selectivity: Cancer Cells vs Normal Cells


TumCG, Tumor cell growth: Click to Expand ⟱
Source:
Type:
Normal cells grow and divide in a regulated manner through the cell cycle, which consists of phases (G1, S, G2, and M).
Cancer cells often bypass these regulatory mechanisms, leading to uncontrolled proliferation. This can result from mutations in genes that control the cell cycle, such as oncogenes (which promote cell division) and tumor suppressor genes (which inhibit cell division).
Scientific Papers found: Click to Expand⟱
2359- SK,    Regulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted delivery
- in-vivo, Liver, NA
TumCG↓, SHK@HA-MPDA achieved tumor-targeted delivery via hyaluronic acid-mediated binding with the tumor-associated CD44, and efficiently arrested colorectal tumor growth
PKM2↓, The inhibition of PKM2 by SHK@HA-MPDA led to the remodeling of the tumor immune microenvironment
EMT↓, reversing EMT by lactate abatement and the suppression of TGFβ signaling
TGF-β↓,
Glycolysis↓, EMT reversal by suppressing glycolysis and lactate production
lactateProd↓,
ATP↓, SHK@HA-MPDA nanosystem efficiently inhibited tetramer PKM2 and further reduced lactate and ATP production

2357- SK,    GTPBP4 promotes hepatocellular carcinoma progression and metastasis via the PKM2 dependent glucose metabolism
- Study, HCC, NA - in-vivo, NA, NA
AntiTum↑, Shikonin exerted a remarkable antitumor effect in many tumors.
GTPBP4↓, We found that, first Shikonin could inhibit the binding of GTPBP4 and PKM2 proteins
PKM2↓,
lactateProd↓, increased lactate production and glucose consumption activity by GTPBP4 overexpression in PLC/PRF/5 and SMMC-7721 cells cells could be fully antagonized by Shikonin
GlucoseCon↓,
Glycolysis↓, Shikonin could suppress HCC growth and glycolysis through inhibiting PKM2 dependent glucose metabolism
E-cadherin↑, Downregulation of E-cadherin in GTPBP4 overexpression PLC/PRF/51 xenografts was also rescued by Shikonin treatment
TumCG↓, We found that Shikonin administration efficiently suppresses tumor growth in orthotopic xenograft mouse models of HCC

2356- SK,    ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment
- in-vitro, Ovarian, CaOV3 - in-vitro, Ovarian, OV90 - in-vivo, NA, NA
PKM2↓, Shikonin effectively inhibits the molecular interaction between ESM1 and PKM2, consequently preventing the formation of PKM2 dimers and thereby inhibiting ovarian cancer glycolysis, fatty acid synthesis and vasculogenic mimicry.
Glycolysis↓, Shikonin inhibited glycolysis in OV90 cells
FASN↓,
lactateProd↓, In both CAOV3 and OV90 cells, the levels of lactic acid were significantly reduced in the ESM1 and Shikonin group when compared to the ESM1-overexpressing group
Warburg↓, Shikonin could repress the interaction between PKM2 and ESM1 and the formation of PKM2 dimers to attenuate OC migration and invasion and VM by driving the Warburg effect in vitro.
TumCG↓, Shikonin itself significantly inhibited tumor growth
VM↓, Shikonin significantly attenuates the OC growth and the VM of OC cells

2230- SK,    Shikonin induces ROS-based mitochondria-mediated apoptosis in colon cancer
- in-vitro, CRC, HCT116 - in-vivo, NA, NA
TumCG↓, shikonin suppressed the growth of colon cancer cells in a dose-dependent manner in vitro and in vivo
Bcl-2↓, Shikonin induced mitochondria-mediated apoptosis, which was regulated by Bcl-2 family proteins.
ROS↑, found that shikonin dose-dependently increased the generation of intracellular ROS in colon cancer cells
Bcl-xL↓, generation of ROS, down-regulated expression of Bcl-2 and Bcl-xL, depolarization of the mitochondrial membrane potential and activation of the caspase cascade
MMP↓,
Casp↑,
selectivity↑, shikonin presented minimal toxicity to non-neoplastic colon cells and no liver injury in xenograft models
cycD1↓, Cyclin D expression was decreased with shikonin treatment
TumCCA↑, induced cell growth inhibition by the induction G1 cell cycle arrest.
eff↓, NAC or GSH could block the shikonin-dependent burst of intracellular ROS

2228- SK,    Shikonin induced Apoptosis Mediated by Endoplasmic Reticulum Stress in Colorectal Cancer Cells
- in-vitro, CRC, HCT116 - in-vitro, CRC, HCT15 - in-vivo, NA, NA
Apoptosis↑, shikonin induced cell apoptosis by down-regulating BCL-2 and activating caspase-3/9 and the cleavage of PARP.
Bcl-2↓,
Casp3↑,
Casp9↑,
cl‑PARP↑,
GRP78/BiP↑, The expression of BiP and the PERK/elF2α/ATF4/CHOP and IRE1α /JNK signaling pathways were upregulated after shikonin treatment.
PERK↑,
eIF2α↑,
ATF4↑,
CHOP↑,
JNK↑,
eff↓, pre-treatment with N-acetyl cysteine significantly reduced the cytotoxicity of shikonin
ER Stress↑, Shikonin induced endoplasmic reticulum stress
ROS↑, Shikonin induced reactive oxygen species-mediated ER stress
TumCG↓, Shikonin suppressed the growth of colorectal cancer cells in vivo

2219- SK,    Shikonin induces apoptosis of HaCaT cells via the mitochondrial, Erk and Akt pathways
- in-vitro, Nor, HaCaT
*MMP↓, Shikonin decreases the Δψm and induces ROS generation
*ROS↑,
*Casp3↑, shikonin significantly increased caspase 3 cleavage, as compared with the untreated cells
*TumCG↓, Shikonin inhibits the growth of HaCaT cells

3047- SK,    Shikonin suppresses colon cancer cell growth and exerts synergistic effects by regulating ADAM17 and the IL-6/STAT3 signaling pathway
- in-vitro, CRC, HCT116 - in-vitro, CRC, SW48
TumCG↓, SKN inhibited colon cancer cell growth, suppressed both constitutive and IL-6-induced STAT3 phosphorylation, and downregulated the expression of ADAM17
p‑STAT3↓,
ADAM17↓,
Apoptosis↑, SKN promoted cell apoptosis, as evidenced by increased expression levels of cleaved caspase-3 and cleaved PARP in both cell lines
Casp3↑,
cl‑PARP↑,
cycD1↓, SKN decreased the expression of cyclin D1 and cyclin E1, thus suggesting the disruption of the cell cycle and the suppression of cell growth
cycE↓,
TumCCA↑,
JAK1?, The inhibitory effects of SKN on the phosphorylation of both JAK1 and JAK2 in the two cell lines were also observed
p‑JAK1↓,
p‑JAK2↓,
p‑eIF2α↑, phosphorylation levels of eIF2α were enhanced by SKN (20 µM) in the HCT116 and SW480 colon cancer cells
eff↓, NAC decreased SKN-induced p-eIF2α expression and reversed the SKN-mediated downregulation of ADAM17 protein expression
ROS↑, suppressed the expression of ADAM17 mediated by ROS-associated p-eIF2α expression in the HCT116 and SW480 colon cancer cells
IL6↓, demonstrated that the antitumor effects of SKN on colon cancer cells were associated with its inhibition of the IL-6/STAT3 signaling pathway.

2009- SK,    Necroptosis inhibits autophagy by regulating the formation of RIP3/p62/Keap1 complex in shikonin-induced ROS dependent cell death of human bladder cancer
- in-vitro, Bladder, NA
TumCG↓, shikonin has a selective inhibitory effect on bladder cancer cells
selectivity↑, and has no toxicity on normal bladder epithelial cells
*toxicity∅,
Necroptosis↑, shikonin induced necroptosis and impaired autophagic flux via ROS generation
ROS↑,
p62↑, accumulation of autophagic biomarker p62 elevated p62/Keap1 complex and activated the Nrf2 signaling pathway to fight against ROS
Keap1↑,
*NRF2↑, activated the Nrf2 signaling pathway to fight against ROS
eff↑, we further combined shikonin with late autophagy inhibitor(chloroquine) to treat bladder cancer and achieved a better inhibitory effect.

1343- SK,    Simple ROS-responsive micelles loaded Shikonin for efficient ovarian cancer targeting therapy by disrupting intracellular redox homeostasis
- in-vitro, Ovarian, A2780S - in-vivo, NA, A2780S
*BioAv↓, clinical use is limited by poor tumor targeting and low bioavailability
ROS↑,
GSH↓,
TumCG↓,

977- SK,    A novel antiestrogen agent Shikonin inhibits estrogen-dependent gene transcription in human breast cancer cells
- in-vitro, BC, T47D - in-vitro, BC, MDA-MB-231 - in-vitro, BC, MCF-7 - in-vitro, Nor, HMEC
TumCG↓, SK inhibits tumor cell growth in estrogen receptor alpha (ERalpha)-positive, but not ERalpha-negative breast cancer cells.
ERα↓, SK inhibits ERa expression, and suppresses ERa signaling
selectivity↑, non-malignant HME cells show undetectable ERa protein (Fig. 2a). Treatment with increased concentrations of SK for 72 h has no effect on cell growth
*toxicity↓, In addition, SK shows low cytoxicity in normal human mammary epithelia cells.

2212- SK,    Shikonin Exerts an Antileukemia Effect against FLT3-ITD Mutated Acute Myeloid Leukemia Cells via Targeting FLT3 and Its Downstream Pathways
- in-vitro, AML, NA
FLT3↓, SHK suppresses the expression and phosphorylation of FLT3 receptors and their downstream molecules
NF-kB↓, Inhibition of the NF-κB/miR-155 pathway is an important mechanism through which SHK kills FLT3-AML cells
miR-155↓,
Diff↑, Moreover, a low concentration of SHK promotes the differentiation of AML cells with FLT3-ITD mutations.
TumCG↓, Finally, SHK could significantly inhibit the growth of MV4-11 cells in leukemia bearing mice.


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 11

Results for Effect on Cancer/Diseased Cells:
ADAM17↓,1,   AntiTum↑,1,   Apoptosis↑,2,   ATF4↑,1,   ATP↓,1,   Bcl-2↓,2,   Bcl-xL↓,1,   Casp↑,1,   Casp3↑,2,   Casp9↑,1,   CHOP↑,1,   cycD1↓,2,   cycE↓,1,   Diff↑,1,   E-cadherin↑,1,   eff↓,3,   eff↑,1,   eIF2α↑,1,   p‑eIF2α↑,1,   EMT↓,1,   ER Stress↑,1,   ERα↓,1,   FASN↓,1,   FLT3↓,1,   GlucoseCon↓,1,   Glycolysis↓,3,   GRP78/BiP↑,1,   GSH↓,1,   GTPBP4↓,1,   IL6↓,1,   JAK1?,1,   p‑JAK1↓,1,   p‑JAK2↓,1,   JNK↑,1,   Keap1↑,1,   lactateProd↓,3,   miR-155↓,1,   MMP↓,1,   Necroptosis↑,1,   NF-kB↓,1,   p62↑,1,   cl‑PARP↑,2,   PERK↑,1,   PKM2↓,3,   ROS↑,5,   selectivity↑,3,   p‑STAT3↓,1,   TGF-β↓,1,   TumCCA↑,2,   TumCG↓,10,   VM↓,1,   Warburg↓,1,  
Total Targets: 52

Results for Effect on Normal Cells:
BioAv↓,1,   Casp3↑,1,   MMP↓,1,   NRF2↑,1,   ROS↑,1,   toxicity↓,1,   toxicity∅,1,   TumCG↓,1,  
Total Targets: 8

Scientific Paper Hit Count for: TumCG, Tumor cell growth
11 Shikonin
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:150  Target#:323  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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