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


Hif1a, HIF1α/HIF1a: Click to Expand ⟱
Source:
Type:
Hypoxia-Inducible-Factor 1A (HIF1A gene, HIF1α, HIF-1α protein product)
-Dominantly expressed under hypoxia(low oxygen levels) in solid tumor cells
-HIF1A induces the expression of vascular endothelial growth factor (VEGF)
-High HIF-1α expression is associated with Poor prognosis
-Low HIF-1α expression is associated with Better prognosis

-Functionally, HIF-1α is reported to regulate glycolysis, whilst HIF-2α regulates genes associated with lipoprotein metabolism.
-Cancer cells produce HIF in response to hypoxia in order to generate more VEGF that promote angiogenesis

Key mediators of aerobic glycolysis regulated by HIF-1α.
-GLUT-1 → regulation of the flux of glucose into cells.
-HK2 → catalysis of the first step of glucose metabolism.
-PKM2 → regulation of rate-limiting step of glycolysis.
-Phosphorylation of PDH complex by PDK → blockage of OXPHOS and promotion of aerobic glycolysis.
-LDH (LDHA): Rapid ATP production, conversion of pyruvate to lactate;

HIF-1α Inhibitors:
-Curcumin: disruption of signaling pathways that stabilize HIF-1α (ie downregulate).
-Resveratrol: downregulate HIF-1α protein accumulation under hypoxic conditions.
-EGCG: modulation of upstream signaling pathways, leading to decreased HIF-1α activity.
-Emodin: reduce HIF-1α expression. (under hypoxia).
-Apigenin: inhibit HIF-1α accumulation.
Scientific Papers found: Click to Expand⟱
3051- SK,    Resveratrol mediates its anti-cancer effects by Nrf2 signaling pathway activation
- Review, Var, NA
Nrf1↑, Resveratrol is a natural compound that can activate the Nrf2 transcription factor
Apoptosis↑, In different cell lines, resveratrol can increase apoptosis and inhibit the proliferation of cancer cells.
TumCP↓,
eff⇅, But there is a controversy on whether activation of Nrf2 is of clinical benefit in cancer therapy or is a carcinogen?
chemoP↑, chemoprevention effects
eff↑, It has also been suggested that reduction in oxidative conditions in cancer cells may enhance the anticancer effects of antineoplastic drugs [4].
VCAM-1↓, Resveratrol was effective on angiogenesis through an inhibitory direct effect on vascular endothelial growth factor (VEGF) generation and also inhibiting the hypoxia-inducible factor (HIF)-1generation and leads to preventing VEGF secretion
Hif1a↓,

3041- SK,    Promising Nanomedicines of Shikonin for Cancer Therapy
- Review, Var, NA
Glycolysis↓, SHK could regulate immunosuppressive tumor microenvironment through inhibiting glycolysis of tumor cells and repolarizing tumor-associated macrophages (TAMs).
TAMS↝,
BioAv↓, HK is a hydrophobic natural molecule with unsatisfactory solubility, rapid intestinal absorption, obvious “first pass” effect, and rapid clearance, leading to low oral bioavailability.
Half-Life↝, SHK displays a half-life of 15.15 ± 1.41 h and Cmax of 0.94 ± 0.11 μg/ml in rats when administered intravenously.
P21↑, Table 1
ERK↓,
ROS↑,
GSH↓,
MMP↓,
TrxR↓,
MMP13↓,
MMP2↓,
MMP9↓,
SIRT2↑,
Hif1a↓,
PKM2↓,
TumCP↓, Inhibit Cell Proliferation
TumMeta↓, Inhibit Cells Metastasis and Invasion
TumCI↓,

2370- SK,    The role of pyruvate kinase M2 in anticancer therapeutic treatments
- Review, Var, NA
Glycolysis↓, In summary, shikonin is able to inhibit tumor growth by suppressing aerobic glycolysis, which is mediated by PKM2 in vivo
PKM2↓,
EGFR↓, another study indicated that shikonin reduced epidermal growth factor receptor, PI3K, p-AKT, Hypoxia inducible factor-1α (HIF-1α) and PKM2 expression levels
PI3K↓,
p‑Akt↓,
Hif1a↓,

965- SK,    Shikonin suppresses proliferation and induces cell cycle arrest through the inhibition of hypoxia-inducible factor-1α signaling
- in-vitro, CRC, HCT116 - in-vitro, CRC, SW-620
Hif1a↓, shikonin inhibited HIF-1α protein synthesis without affecting the expression of HIF-1α mRNA or degrading HIF-1α protein
ROS↓, shikonin resulted in a significant decrease of hypoxia-induced ROS production in HCT116 and SW620 cells
mTOR↓,
p70S6↓,
4E-BP1↓,
eIF2α↓,
TumCCA↑, HCT116 cells
TumCP↓, HCT116 and SW620
Half-Life↝, shikonin-treated cells (Fig. S1), showing the half-life was around 50 min in HCT116 and SW620 cells.

2197- SK,    Shikonin derivatives for cancer prevention and therapy
- Review, Var, NA
ROS↑, This compound accumulates in the mitochondria, which leads to the generation of reactive oxygen species (ROS), and deregulates intracellular Ca2+ levels.
Ca+2↑,
BAX↑, shikonin alone by increasing the expression of the pro-apoptotic Bax protein and decreasing the expression of the anti-apoptotic Bcl2 protein
Bcl-2↓,
MMP9↓, This treatment also inhibited metastasis by decreasing the expression of MMP-9 and NF-kB p65 without affecting MMP-2 expression.
NF-kB↓,
PKM2↓, Figure 4
Hif1a↓,
NRF2↓,
P53↑,
DNMT1↓,
MDR1↓,
COX2↓,
VEGF↓,
EMT↓,
MMP7↓,
MMP13↓,
uPA↓,
RIP1↑,
RIP3↑,
Casp3↑,
Casp7↑,
Casp9↑,
P21↓,
DFF45↓,
TRAIL↑,
PTEN↑,
mTOR↓,
AR↓,
FAK↓,
Src↓,
Myc↓,
RadioS↑, shikonin acted as a radiosensitizer because of the high ROS production it induced.

2195- SK,    Shikonin induces ferroptosis in osteosarcomas through the mitochondrial ROS-regulated HIF-1α/HO-1 axis
- in-vitro, OS, NA
TumCP↓, At a low dose, Shikonin inhibits OS progression and has a excellent biosafety.
Ferroptosis↓, Shikonin induces ferroptosis in OS cel
Hif1a↑, Shikonin upregualtes HIF-1α/HO-1 axis to produce excess Fe2+ which leads to ROS accumulation on OS cell, followed by ferroptosis.
HO-1↑,
Iron↑,
ROS↑,
GSH/GSSG↓, while simultaneously reducing the GSH/GSSG ratio and GPX4 and SLC7A11 expression
GPx4↓,

2194- SK,    Efficacy of Shikonin against Esophageal Cancer Cells and its possible mechanisms in vitro and in vivo
- in-vitro, ESCC, Eca109 - in-vitro, ESCC, EC9706 - in-vivo, NA, NA
tumCV↓, Shikonin reduced esophageal cancer cells viability and induced cell cycle arrest and apoptosis.
TumCCA↑,
Apoptosis↑,
EGFR↓, Shikonin decreased EGFR, PI3K, p-AKT, HIF1α and PKM2 expression
PI3K↓,
Hif1a↓,
PKM2↓,
cycD1↓, shikonin reduced the expression of PKM2, HIF1α and cyclinD1 in tumor tissues
AntiTum↑, shikonin has a powerful antitumor effect in vivo.

2193- SK,    Shikonin Suppresses Lymphangiogenesis via NF-κB/HIF-1α Axis Inhibition
- in-vitro, Nor, HMVEC-dLy
*NF-kB↓, shikonin decreased nuclear factor-kappaB (NF-κB) activation
*Hif1a↓, reduced both mRNA and protein levels of hypoxia-inducible factor-1 (HIF-1)α.
other↓, shikonin inhibits lymphangiogenesis in vitro by interfering the NF-κB/HIF-1α pathway and involves in suppression of VEGF-C and VEGFR-3 mRNA expression.


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 8

Results for Effect on Cancer/Diseased Cells:
4E-BP1↓,1,   p‑Akt↓,1,   AntiTum↑,1,   Apoptosis↑,2,   AR↓,1,   BAX↑,1,   Bcl-2↓,1,   BioAv↓,1,   Ca+2↑,1,   Casp3↑,1,   Casp7↑,1,   Casp9↑,1,   chemoP↑,1,   COX2↓,1,   cycD1↓,1,   DFF45↓,1,   DNMT1↓,1,   eff↑,1,   eff⇅,1,   EGFR↓,2,   eIF2α↓,1,   EMT↓,1,   ERK↓,1,   FAK↓,1,   Ferroptosis↓,1,   Glycolysis↓,2,   GPx4↓,1,   GSH↓,1,   GSH/GSSG↓,1,   Half-Life↝,2,   Hif1a↓,6,   Hif1a↑,1,   HO-1↑,1,   Iron↑,1,   MDR1↓,1,   MMP↓,1,   MMP13↓,2,   MMP2↓,1,   MMP7↓,1,   MMP9↓,2,   mTOR↓,2,   Myc↓,1,   NF-kB↓,1,   Nrf1↑,1,   NRF2↓,1,   other↓,1,   P21↓,1,   P21↑,1,   P53↑,1,   p70S6↓,1,   PI3K↓,2,   PKM2↓,4,   PTEN↑,1,   RadioS↑,1,   RIP1↑,1,   RIP3↑,1,   ROS↓,1,   ROS↑,3,   SIRT2↑,1,   Src↓,1,   TAMS↝,1,   TRAIL↑,1,   TrxR↓,1,   TumCCA↑,2,   TumCI↓,1,   TumCP↓,4,   tumCV↓,1,   TumMeta↓,1,   uPA↓,1,   VCAM-1↓,1,   VEGF↓,1,  
Total Targets: 71

Results for Effect on Normal Cells:
Hif1a↓,1,   NF-kB↓,1,  
Total Targets: 2

Scientific Paper Hit Count for: Hif1a, HIF1α/HIF1a
8 Shikonin
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:150  Target#:143  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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