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


PI3K, Phosphatidylinositide-3-Kinases: Click to Expand ⟱
Source: HalifaxProj(inhibit) CGL-CS
Type:
Phosphatidylinositol 3-kinase (PtdIns3K or PI3K) is a family of enzymes that play a crucial role in cell signaling pathways, particularly in the regulation of cell growth, survival, and metabolism. The PI3K pathway is one of the most frequently altered pathways in human cancer. Inhibition of the PI3K pathway has been explored as a therapeutic strategy for cancer treatment. Several PI3K inhibitors have been developed and are currently being tested in clinical trials. These inhibitors can target specific components of the pathway, such as PI3K, AKT, or mTOR.

Class I phosphoinositide 3-kinase (PI3K)
Class III PtdIns3K
In contrast to the class III PtdIns3K as a positive regulator of autophagy, class I PI3K-AKT signaling has an opposing effect on the initiation of autophagy.

PI3K inhibitors include:
-Idelalisib , Copanlisib, Alpelisib
-LY294002?
-Wortmannin: potent PI3K inhibitor, has some associated toxicity.
-Quercetin:
-Curcumin
-Resveratrol
-Epigallocatechin Gallate (EGCG)
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↓,

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

2220- SK,    Shikonin Alleviates Gentamicin-Induced Renal Injury in Rats by Targeting Renal Endocytosis, SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt Cascades
- in-vivo, Nor, NA
*RenoP↑, Shikonin significantly and dose-dependently alleviated gentamicin-induced renal injury, as revealed by restoring normal kidney function and histological architecture.
*ROS↓, Shikonin Defended against Renal Oxidative Stress and Activated the SIRT1/Nrf2/HO-1 Cascades in Rats with Gentamicin-Induced Renal Damage
*SIRT1↓,
*NRF2↑,
*HO-1↑,
*GSH↑, significant rise in GSH, TAC levels, and SOD activity, as well as SIRT1, Nrf2, and HO-1 protein levels
*TAC↑,
*SOD↑,
*MDA↓, significant decrease in the renal MDA, NO, and iNOS
*NO↓,
*iNOS↓,
*NHE3↑, shikonin treatment significantly and dose-dependently enhanced the reduced NHE3 level and mRNA expression induced by repeated gentamicin injections,
*PI3K↑, in the current study, shikonin treatment of the gentamicin-injected groups increased PI3K

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↓,

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↓,

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.

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: 9

Results for Effect on Cancer/Diseased Cells:
Akt↓,6,   p‑Akt↓,1,   angioG↓,1,   AntiCan↑,1,   AntiTum↑,1,   Apoptosis?,1,   Apoptosis↑,5,   ATF2↓,1,   ATP↓,2,   BAX↑,1,   BioAv↓,1,   Ca+2↓,1,   Casp3↑,2,   proCasp3↑,1,   cycD1↓,1,   eff↓,1,   eff↑,1,   EGFR↓,4,   EGR1↑,1,   ERK↓,1,   p‑ERK↓,1,   FAK↓,1,   FOXO3↑,1,   GlucoseCon↓,1,   GLUT1↓,1,   Glycolysis↓,2,   GRP58↓,1,   GSH↓,1,   Half-Life↓,1,   Hif1a↓,2,   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↓,1,   p38↑,1,   p‑p38↑,1,   P53↑,1,   cl‑PARP↑,1,   PI3K↓,8,   PKM2↓,5,   PYCR1↓,1,   RIP1↓,1,   RIP1↑,1,   RIP3↓,1,   RIP3↑,1,   ROS↑,3,   SIRT1↑,1,   Src↓,1,   Src↑,1,   TIMP1↑,1,   TrxR1↓,1,   TumAuto↑,2,   TumCCA↑,2,   TumCI↓,1,   TumCMig↓,2,   TumCP↓,2,   tumCV↓,1,   VEGF↓,1,  
Total Targets: 68

Results for Effect on Normal Cells:
Apoptosis↓,1,   GSH↑,1,   hepatoP↑,1,   HO-1↑,1,   IL10↓,1,   IL17↓,1,   IL6↓,1,   IL8↓,1,   Inflam↓,1,   iNOS↓,1,   MDA↓,1,   NHE3↑,1,   NO↓,1,   NRF2↑,1,   PI3K↑,1,   RenoP↑,2,   ROS↓,1,   SIRT1↓,1,   SOD↑,1,   TAC↑,1,   TNF-α↓,1,  
Total Targets: 21

Scientific Paper Hit Count for: PI3K, Phosphatidylinositide-3-Kinases
9 Shikonin
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:150  Target#:252  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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