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


Akt, PKB-Protein kinase B: Click to Expand ⟱
Source: HalifaxProj(inhibit)
Type:
Akt1 is involved in cellular survival pathways, by inhibiting apoptotic processes; Akt2 is an important signaling molecule in the insulin signaling pathway. It is required to induce glucose transport.

Inhibitors:
-Curcumin: downregulate AKT phosphorylation and signaling.
-Resveratrol
-Quercetin: inhibit the PI3K/AKT pathway.
-Epigallocatechin Gallate (EGCG)
-Luteolin and Apigenin: inhibit AKT phosphorylation


Scientific Papers found: Click to Expand⟱
2360- SK,    Shikonin inhibits growth, invasion and glycolysis of nasopharyngeal carcinoma cells through inactivating the phosphatidylinositol 3 kinase/AKT signal pathway
- in-vitro, NPC, HONE1 - in-vitro, NPC, SUNE-1
TumCP↓, Shikonin treatment effectively suppressed cell proliferation and induced obvious cell apoptosis compared with the control.
Apoptosis↑,
TumCMig↓, Shikonin treatment suppressed cell migration and invasion effectively.
TumCI↓,
GlucoseCon↓, Shikonin treatment suppressed cell glucose uptake, lactate release and ATP level.
lactateProd↓,
ATP↓,
PKM2↓, activity of PKM2 was also largely inhibited by Shikonin
PI3K↓, PI3K/AKT signal pathway was inactivated by Shikonin treatment
Akt↓,
MMP3↓, MMP-3 and MMP-9 was decreased and the expression of TIMP was increased by Shikonin in HONE1 and SUNE-1 cells
MMP9↓,
TIMP1↑,

2355- SK,    Pharmacological properties and derivatives of shikonin-A review in recent years
- Review, Var, NA
AntiCan↑, anticancer effects on various types of cancer by inhibiting cell proliferation and migration, inducing apoptosis, autophagy, and necroptosis.
TumCP↓,
TumCMig↓,
Apoptosis↑,
TumAuto↑,
Necroptosis↑,
ROS↑, Shikonin also triggers Reactive Oxygen Species (ROS) generation
TrxR1↓, inhibiting the activation of TrxR1, PKM2, RIP1/3, Src, and FAK
PKM2↓,
RIP1↓,
RIP3↓,
Src↓,
FAK↓,
PI3K↓, modulating the PI3K/AKT/mTOR and MAPKs signaling;
Akt↓, shikonin induced a dose-dependent reduction of miR-19a to inhibit the activity of PI3K/AKT/mTOR pathway
mTOR↓,
GRP58↓, shikonin induced apoptosis in human myeloid cell line HL-60 cells through downregulating the expression of ERS protein ERP57 (42).
MMPs↓, hikonin suppressed cell migration through inhibiting the NF-κB pathway and reducing the expression of MMP-2 and MMP-9
ATF2↓, shikonin inhibited cell proliferation and tumor growth through suppressing the ATF2 pathway
cl‑PARP↑, shikonin significantly upregulated the expression of apoptosis-related proteins cleaved PARP and caspase-3 and increased cell apoptosis through increasing the phosphorylation of p38 MAPK and JNK, and inhibiting the phosphorylation of ERK
Casp3↑,
p‑p38↑,
p‑JNK↑,
p‑ERK↓,

2226- SK,    Shikonin, a Chinese plant-derived naphthoquinone, induces apoptosis in hepatocellular carcinoma cells through reactive oxygen species: A potential new treatment for hepatocellular carcinoma
- in-vitro, HCC, HUH7 - in-vitro, HCC, Bel-7402
selectivity↑, shikonin induced apoptosis of Huh7 and BEL7402 but not nontumorigenic cells.
ROS↑, ROS generation was detected
eff↓, ROS scavengers completely inhibited shikonin-induced apoptosis, indicating that ROS play an essential role
Akt↓, downregulation of Akt and RIP1/NF-κB activity was found to be involved in shikonin-induced apoptosis
RIP1↓,
NF-kB↓,

2225- SK,    Shikonin protects skin cells against oxidative stress and cellular dysfunction induced by fine particulate matter
- in-vitro, Nor, HaCaT
*antiOx↑, antioxidant capabilities of shikonin and its ability to protect human keratinocytes from oxidative stress induced by fine particulate matter
*ROS↓, 3 µM was nontoxic to human keratinocytes and effectively scavenged reactive oxygen species (ROS) while increasing the production of reduced glutathione (GSH).
*GSH↑,
*GCLC↑, Shikonin increased the expression of GCLC and GSS via AKT and NRF2 activation
*GSS↑,
*Akt↑,
*NRF2↑,

2224- SK,    Shikonin induces apoptosis and autophagy via downregulation of pyrroline-5-carboxylate reductase1 in hepatocellular carcinoma cells
- in-vitro, HCC, SMMC-7721 cell - in-vitro, HCC, HUH7 - in-vitro, HCC, HepG2
PYCR1↓, SK may induce apoptosis and autophagy by reducing the expression of PYCR1 and suppressing PI3K/Akt/mTOR
PI3K↓,
Akt↓,
mTOR↓,
eff↑, SK reinforces its anti-tumor effects by downregulating PYCR1 in HCC cells

3049- SK,    Shikonin Attenuates Chronic Cerebral Hypoperfusion-Induced Cognitive Impairment by Inhibiting Apoptosis via PTEN/Akt/CREB/BDNF Signaling
- in-vivo, Nor, NA - NA, Stroke, NA
*neuroP↑, Shikonin (SK) exerts neuroprotective effects
*p‑PTEN↓, SK administration reversed the upregulation of p-PTEN and the downregulation of p-Akt, p-CREB, and BDNF
*p‑Akt↑,
*Bcl-2↑, SK treatment upregulated the expression of bcl-2 and downregulated the expression of bax, thereby elevating the bcl-2/bax ratio.
*BAX↓,
*cognitive↑, , consequently improving cognitive impairment.

3043- SK,    Shikonin Induces Apoptosis by Inhibiting Phosphorylation of IGF-1 Receptor in Myeloma Cells.
- in-vitro, Melanoma, RPMI-8226
IGF-1↓, Shikonin Induces Apoptosis by Inhibiting Phosphorylation of IGF-1 Receptor in Myeloma Cells
Apoptosis↑, Shikonin suppressed the cellular growth of RPMI8226 and IM9 myeloma cells, via induction of apoptosis in a dose (0–1 μM)- and time (0–24 h)-dependent manner.
TumCCA↑, Treatment with 0.5 μM Shikonin rapidly increased the population of cells in the G0/G1 phase with reduction of cells in the S phase
MMP↓, Shikonin-induced apoptosis was in association with the loss of mitochondrial transmembrane potentials, and activation of caspase-3.
Casp3↑,
P53↑, Expression of p53 and Bax proteins was increased with down-regulation of Mcl-1 protein
BAX↑,
Mcl-1↓,
EGFR↓, Shikonin has reported to be an inhibitor of protein tyrosine kinase such as EGFR, v-Src, and KDR/Flk-1.
Src↑,
KDR/FLK-1↓,
p‑IGF-1↓, Shikonin inhibited phosphorylation of IGF-1 receptor as early as 30 min with inhibition of PI3K/Akt signaling
PI3K↓,
Akt↓,

2469- SK,    Shikonin induces the apoptosis and pyroptosis of EGFR-T790M-mutant drug-resistant non-small cell lung cancer cells via the degradation of cyclooxygenase-2
- in-vitro, Lung, H1975
Apoptosis↑, Shikonin induced cell apoptosis and pyroptosis by triggering the activation of the caspase cascade and cleavage of poly (ADP-ribose) polymerase and gasdermin E by elevating intracellular ROS levels
Pyro↑,
Casp↑,
cl‑PARP↑,
GSDME↑,
ROS↑,
COX2↓, shikonin induced the degradation of COX-2 via the proteasome pathway, thereby decreasing COX-2 protein level and enzymatic activity and subsequently inhibiting the downstream PDK1/Akt and Erk1/2 signaling pathways through the induction of ROS produc
PDK1↓,
Akt↓,
ERK↓,
eff↓, Notably, COX-2 overexpression attenuated shikonin-induced apoptosis and pyroptosis
eff↓, NAC pre-treatment inhibited the shikonin-induced activation of the caspase cascade (caspase-8/9/3) and cleavage of PARP and GSDME in H1975 cells
eff↑, Celecoxib augmented the cytotoxic effects of shikonin by promoting the apoptosis and pyroptosis of H1975 cells

2415- SK,    Shikonin induces programmed death of fibroblast synovial cells in rheumatoid arthritis by inhibiting energy pathways
- in-vivo, Arthritis, NA
Apoptosis?, shikonin induced apoptosis and autophagy in RA-FLSs by activating the production of reactive oxygen species (ROS) and inhibiting intracellular ATP levels, glycolysis-related proteins, and the PI3K-AKT-mTOR signaling pathway.
TumAuto↑,
ROS↑,
ATP↓,
Glycolysis↓, shikonin can inhibit RA-glycolysis in FLSs
PI3K↓,
Akt↓,
mTOR↓,
*Apoptosis↓, Shikonin can significantly reduce the expression of apoptosis-related proteins, paw swelling in rat arthritic tissues, and the levels of inflammatory factors in peripheral blood, such as TNF-α, IL-6, IL-8, IL-10, IL-17A, and IL-1β while showing less
*Inflam↓,
*TNF-α↓,
*IL6↓,
*IL8↓,
*IL10↓,
*IL17↓,
*hepatoP↑, while showing less toxicity to the liver and kidney.
*RenoP↑,
PKM2↓, The expression of glycogen proteins PKM2, GLUT1, and HK2 decreased with increasing concentrations of shikonin
GLUT1↓,
HK2↓,

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↓,

1281- SK,    Enhancement of NK cells proliferation and function by Shikonin
- in-vivo, Colon, Caco-2
Perforin↑,
GranB↑,
p‑ERK↑,
p‑Akt↑,
NK cell↑, Shikonin had no effect on cells proliferation at 24 h, and enhanced cells proliferation at 48 h and 72 h at the dose of 1.56 ng/ml to 6.25 ng/ml. Meanwhile, Shikonin inhibits the cell proliferation at 100.0 ng/ml
eff↝, Meanwhile, Shikonin inhibits the cell proliferation at 100.0 ng/ml

2188- SK,    Molecular mechanism of shikonin inhibiting tumor growth and potential application in cancer treatment
- Review, Var, NA
ROS↑, their induction of reactive oxygen species production, inhibition of EGFR and PI3K/AKT signaling pathway activation, inhibition of angiogenesis and induction of apoptosis and necroptosis
EGFR↓,
PI3K↓,
Akt↓,
angioG↓,
Apoptosis↑,
Necroptosis↑,
GSH↓, leading to the increased consumption of reduced glutathione (GSH) and increased Ca2+ concentration in the cells and destroying the mitochondrial membrane potential.
Ca+2↓,
MMP↓,
ERK↓, 24 h of treatment with shikonin, ERK 1/2 and AKT activities were significantly inhibited, and p38 activity was upregulated, which ultimately led to pro-caspase-3 cleavage and triggered the apoptosis of GC cells.
p38↑,
proCasp3↑,
eff↓, pretreated with the ROS scavengers NAC and GSH before treatment with shikonin, the production of ROS was significantly inhibited, the cytotoxicity of shikonin was attenuated
VEGF↓, shikonin can inhibit the expression of VEGF
FOXO3↑, Activated FOXO3a/EGR1/SIRT1 signaling
EGR1↑,
SIRT1↑,
RIP1↑, Upregulation of RIP1 and RIP3
RIP3↑,
BioAv↓, limitations caused by its poor water solubility, it has a short half-life and nonselective biological distribution
NF-kB↓, Shikonin can also prevent the activation of NF-κB by AKT and then downregulate the expression of Bcl-xl,
Half-Life↓, due to the limitations caused by its poor water solubility, it has a short half-life and nonselective biological distribution.


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 12

Results for Effect on Cancer/Diseased Cells:
Akt↓,8,   p‑Akt↓,1,   p‑Akt↑,1,   angioG↓,1,   AntiCan↑,1,   Apoptosis?,1,   Apoptosis↑,5,   ATF2↓,1,   ATP↓,2,   BAX↑,1,   BioAv↓,1,   Ca+2↓,1,   Casp↑,1,   Casp3↑,2,   proCasp3↑,1,   COX2↓,1,   eff↓,4,   eff↑,2,   eff↝,1,   EGFR↓,3,   EGR1↑,1,   ERK↓,2,   p‑ERK↓,1,   p‑ERK↑,1,   FAK↓,1,   FOXO3↑,1,   GlucoseCon↓,1,   GLUT1↓,1,   Glycolysis↓,2,   GranB↑,1,   GRP58↓,1,   GSDME↑,1,   GSH↓,1,   Half-Life↓,1,   Hif1a↓,1,   HK2↓,1,   IGF-1↓,1,   p‑IGF-1↓,1,   p‑JNK↑,1,   KDR/FLK-1↓,1,   lactateProd↓,1,   Mcl-1↓,1,   MMP↓,2,   MMP3↓,1,   MMP9↓,1,   MMPs↓,1,   mTOR↓,3,   Necroptosis↑,2,   NF-kB↓,2,   NK cell↑,1,   p38↑,1,   p‑p38↑,1,   P53↑,1,   cl‑PARP↑,2,   PDK1↓,1,   Perforin↑,1,   PI3K↓,7,   PKM2↓,4,   PYCR1↓,1,   Pyro↑,1,   RIP1↓,2,   RIP1↑,1,   RIP3↓,1,   RIP3↑,1,   ROS↑,5,   selectivity↑,1,   SIRT1↑,1,   Src↓,1,   Src↑,1,   TIMP1↑,1,   TrxR1↓,1,   TumAuto↑,2,   TumCCA↑,1,   TumCI↓,1,   TumCMig↓,2,   TumCP↓,2,   VEGF↓,1,  
Total Targets: 77

Results for Effect on Normal Cells:
Akt↑,1,   p‑Akt↑,1,   antiOx↑,1,   Apoptosis↓,1,   BAX↓,1,   Bcl-2↑,1,   cognitive↑,1,   GCLC↑,1,   GSH↑,1,   GSS↑,1,   hepatoP↑,1,   IL10↓,1,   IL17↓,1,   IL6↓,1,   IL8↓,1,   Inflam↓,1,   neuroP↑,1,   NRF2↑,1,   p‑PTEN↓,1,   RenoP↑,1,   ROS↓,1,   TNF-α↓,1,  
Total Targets: 22

Scientific Paper Hit Count for: Akt, PKB-Protein kinase B
12 Shikonin
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:150  Target#:4  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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