Database Query Results : Shikonin, ,

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


Scientific Papers found: Click to Expand⟱
2229- SK,    Shikonin induces apoptosis and prosurvival autophagy in human melanoma A375 cells via ROS-mediated ER stress and p38 pathways
- in-vitro, Melanoma, A375
"highlight2" >Apoptosis↑, Shikonin induces apoptosis and autophagy in A375 cells and inhibits their proliferation
"highlight2" >TumAuto↑,
"highlight2" >TumCP↓,
"highlight2" >TumCCA↑, Shikonin caused G2/M phase arrest through upregulation of p21 and downregulation of cyclin B1
"highlight2" >P21↑,
"highlight2" >cycD1↓,
"highlight2" >ER Stress↑, Shikonin significantly triggered ER stress-mediated apoptosis by upregulating the expression of p-eIF2α, CHOP, and cleaved caspase-3.
"highlight2" >p‑eIF2α↑,
"highlight2" >CHOP↑,
"highlight2" >cl‑Casp3↑,
"highlight2" >p38↑, induced protective autophagy by activating the p38 pathway, followed by an increase in the levels of p-p38, LC3B-II, and Beclin 1
"highlight2" >LC3B-II↑,
"highlight2" >Beclin-1↑,
"highlight2" >ROS↑, Shikonin increased the production of reactive oxygen species
"highlight2" >eff↓, NAC treatment significantly decreased the expression of p-p38, LC3B-II, and Beclin 1.

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
"highlight2" >TumCP↓, Shikonin treatment effectively suppressed cell proliferation and induced obvious cell apoptosis compared with the control.
"highlight2" >Apoptosis↑,
"highlight2" >TumCMig↓, Shikonin treatment suppressed cell migration and invasion effectively.
"highlight2" >TumCI↓,
"highlight2" >GlucoseCon↓, Shikonin treatment suppressed cell glucose uptake, lactate release and ATP level.
"highlight2" >lactateProd↓,
"highlight2" >ATP↓,
"highlight2" >PKM2↓, activity of PKM2 was also largely inhibited by Shikonin
"highlight2" >PI3K↓, PI3K/AKT signal pathway was inactivated by Shikonin treatment
"highlight2" >Akt↓,
"highlight2" >MMP3↓, MMP-3 and MMP-9 was decreased and the expression of TIMP was increased by Shikonin in HONE1 and SUNE-1 cells
"highlight2" >MMP9↓,
"highlight2" >TIMP1↑,

2359- SK,    Regulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted delivery
- in-vivo, Liver, NA
"highlight2" >TumCG↓, SHK@HA-MPDA achieved tumor-targeted delivery via hyaluronic acid-mediated binding with the tumor-associated CD44, and efficiently arrested colorectal tumor growth
"highlight2" >PKM2↓, The inhibition of PKM2 by SHK@HA-MPDA led to the remodeling of the tumor immune microenvironment
"highlight2" >EMT↓, reversing EMT by lactate abatement and the suppression of TGFβ signaling
"highlight2" >TGF-β↓,
"highlight2" >Glycolysis↓, EMT reversal by suppressing glycolysis and lactate production
"highlight2" >lactateProd↓,
"highlight2" >ATP↓, SHK@HA-MPDA nanosystem efficiently inhibited tetramer PKM2 and further reduced lactate and ATP production

2358- SK,    SIRT1 improves lactate homeostasis in the brain to alleviate parkinsonism via deacetylation and inhibition of PKM2
- in-vivo, Park, NA
"highlight2" >*eff↑, inhibition of PKM2 by shikonin or PKM2-IN-1 alleviates parkinsonism in mice
"highlight2" >*PKM2↓,
"highlight2" >*motorD↑, Behavioral tests showed that shikonin treatment improved the performance on rotarod, tail suspension, and olfaction (Figure 7B).
"highlight2" >*lactateProd↓, Lactate in the CSF was reduced in shikonin-treated A30P mice

2357- SK,    GTPBP4 promotes hepatocellular carcinoma progression and metastasis via the PKM2 dependent glucose metabolism
- Study, HCC, NA - in-vivo, NA, NA
"highlight2" >AntiTum↑, Shikonin exerted a remarkable antitumor effect in many tumors.
"highlight2" >GTPBP4↓, We found that, first Shikonin could inhibit the binding of GTPBP4 and PKM2 proteins
"highlight2" >PKM2↓,
"highlight2" >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
"highlight2" >GlucoseCon↓,
"highlight2" >Glycolysis↓, Shikonin could suppress HCC growth and glycolysis through inhibiting PKM2 dependent glucose metabolism
"highlight2" >E-cadherin↑, Downregulation of E-cadherin in GTPBP4 overexpression PLC/PRF/51 xenografts was also rescued by Shikonin treatment
"highlight2" >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
"highlight2" >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.
"highlight2" >Glycolysis↓, Shikonin inhibited glycolysis in OV90 cells
"highlight2" >FASN↓,
"highlight2" >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
"highlight2" >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.
"highlight2" >TumCG↓, Shikonin itself significantly inhibited tumor growth
"highlight2" >VM↓, Shikonin significantly attenuates the OC growth and the VM of OC cells

2355- SK,    Pharmacological properties and derivatives of shikonin-A review in recent years
- Review, Var, NA
"highlight2" >AntiCan↑, anticancer effects on various types of cancer by inhibiting cell proliferation and migration, inducing apoptosis, autophagy, and necroptosis.
"highlight2" >TumCP↓,
"highlight2" >TumCMig↓,
"highlight2" >Apoptosis↑,
"highlight2" >TumAuto↑,
"highlight2" >Necroptosis↑,
"highlight2" >ROS↑, Shikonin also triggers Reactive Oxygen Species (ROS) generation
"highlight2" >TrxR1↓, inhibiting the activation of TrxR1, PKM2, RIP1/3, Src, and FAK
"highlight2" >PKM2↓,
"highlight2" >RIP1↓,
"highlight2" >RIP3↓,
"highlight2" >Src↓,
"highlight2" >FAK↓,
"highlight2" >PI3K↓, modulating the PI3K/AKT/mTOR and MAPKs signaling;
"highlight2" >Akt↓, shikonin induced a dose-dependent reduction of miR-19a to inhibit the activity of PI3K/AKT/mTOR pathway
"highlight2" >mTOR↓,
"highlight2" >GRP58↓, shikonin induced apoptosis in human myeloid cell line HL-60 cells through downregulating the expression of ERS protein ERP57 (42).
"highlight2" >MMPs↓, hikonin suppressed cell migration through inhibiting the NF-κB pathway and reducing the expression of MMP-2 and MMP-9
"highlight2" >ATF2↓, shikonin inhibited cell proliferation and tumor growth through suppressing the ATF2 pathway
"highlight2" >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
"highlight2" >Casp3↑,
"highlight2" >p‑p38↑,
"highlight2" >p‑JNK↑,
"highlight2" >p‑ERK↓,

2354- SK,    PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation
- in-vivo, Sepsis, NA
"highlight2" >PKM2↓, Shikonin is a potent PKM2 inhibitor in cancer cells and macrophages
"highlight2" >*PKM2↓,
"highlight2" >*IL1β↓, Shikonin dose-dependently inhibited IL-1β, IL-18 and HMGB1 release in activated BMDMs following treatment with NLRP3 inflammasome activator (for example, ATP) or AIM2 inflammasome activator
"highlight2" >*IL18↓,
"highlight2" >*HMGB1↓,
"highlight2" >*Casp1↓, shikonin significantly inhibited caspase-1 activation triggered by stimulation with ATP
"highlight2" >*NLRP3↓, pharmacologic inhibition of PKM2 by shikonin selectively suppresses NLRP3 and AIM2 inflammasome activation.
"highlight2" >*AIM2↓,
"highlight2" >*p‑eIF2α↓, Shikonin inhibited EIF2AK2 phosphorylation (Fig. 6a) and caspase-1 activity (Fig. 6b) in PMs obtained from mice subjected to lethal endotoxemia or polymicrobial sepsis.
"highlight2" >*Sepsis↓,

2234- SK,    Shikonin Suppresses Cell Tumorigenesis in Gastric Cancer Associated with the Inhibition of c-Myc and Yap-1
- in-vitro, GC, NA
"highlight2" >TumCP↓, proliferation rate, migration, and invasion ability of the gastric cancer cell group decreased significantly after shikonin intervention for 24h
"highlight2" >TumCI↓,
"highlight2" >TumCMig↓,
"highlight2" >cMyc↓, expression levels of c-Myc and Yap-1 in gastric cancer cells were found to be significantly decreased after shikonin intervention
"highlight2" >YAP/TEAD↓,

2233- SK,    Clinical trial on the effects of shikonin mixture on later stage lung cancer
- Trial, Lung, NA
"highlight2" >TumVol↓, tumors were reduced over 25% in diameter
"highlight2" >Remission↑, The effective rate was 63.3%, remission rate 36.9%, survival rate of one year 47.3%.
"highlight2" >OS↑,
"highlight2" >QoL↑, After treatment the life quality of patients were greatly improved
"highlight2" >Weight↑, The patients got better appetite and their body weights were increased
"highlight2" >*toxicity∅, It had no harmful effects on peripheral blood picture, heart, kidney and liver. Shikonin mixture is safe and effective for later-stage cancer

2232- SK,    Shikonin Induces Autophagy and Apoptosis in Esophageal Cancer EC9706 Cells by Regulating the AMPK/mTOR/ULK Axis
- in-vitro, ESCC, EC9706
"highlight2" >tumCV↓, Shikonin exposure repressed cell viability and migration and invasion capabilities and caused EC9706 cell autophagy and apoptosis by activating the AMPK/mTOR/ULK axis.
"highlight2" >TumCMig↓,
"highlight2" >TumCI↓,
"highlight2" >TumAuto↑,
"highlight2" >Apoptosis↑,
"highlight2" >Bcl-2↓, Bcl-2 protein expressions were decreased; nevertheless, the protein expression of Bax, cleaved caspase3, cleaved caspase-8, and cleaved PARP were elevated with increasing concentrations of shikonin
"highlight2" >BAX↑,
"highlight2" >cl‑Casp3↑,
"highlight2" >cl‑Casp8↑,
"highlight2" >cl‑PARP↑,
"highlight2" >AMPK↑, Shikonin-Induced Autophagy and Apoptosis Through Activation of AMPK/mTOR/ULK Pathway
"highlight2" >mTOR↑,
"highlight2" >TumVol↓, The tumor diameter is reduced by more than 25%, the response rate is 37%, and the 1-year survival rate is 47%
"highlight2" >OS↑,
"highlight2" >LC3I↑, Similarly, shikonin can upregulate the protein expression of LC3 in EC9706 cells

2231- SK,    Shikonin Exerts Cytotoxic Effects in Human Colon Cancers by Inducing Apoptotic Cell Death via the Endoplasmic Reticulum and Mitochondria-Mediated Pathways
- in-vitro, CRC, SNU-407
"highlight2" >Apoptosis↑, Shikonin induced apoptotic cell death by activating mitogen-activated protein kinase family members
"highlight2" >ER Stress↑, apoptotic process was mediated by the activation of endoplasmic reticulum (ER) stress
"highlight2" >PERK↑, leading to activation of the PERK/elF2α/CHOP apoptotic pathway, and mitochondrial Ca2+ accumulation.
"highlight2" >eIF2α↑,
"highlight2" >CHOP↑,
"highlight2" >mt-Ca+2↑,
"highlight2" >MMP↓, Shikonin increased mitochondrial membrane depolarization
"highlight2" >Bcl-2↓, decrease in B cell lymphoma (Bcl)-2 and an increase in Bcl-2-associated X protein, and subsequently, increased expression of cleaved forms of caspase-9 and -3.
"highlight2" >Casp3↑,
"highlight2" >Casp9↑,
"highlight2" >ERK↑, Shikonin treatment activated ERK, JNK, and p38 MAPK in a time-dependent manner
"highlight2" >JNK↑,
"highlight2" >p38↓,

2230- SK,    Shikonin induces ROS-based mitochondria-mediated apoptosis in colon cancer
- in-vitro, CRC, HCT116 - in-vivo, NA, NA
"highlight2" >TumCG↓, shikonin suppressed the growth of colon cancer cells in a dose-dependent manner in vitro and in vivo
"highlight2" >Bcl-2↓, Shikonin induced mitochondria-mediated apoptosis, which was regulated by Bcl-2 family proteins.
"highlight2" >ROS↑, found that shikonin dose-dependently increased the generation of intracellular ROS in colon cancer cells
"highlight2" >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
"highlight2" >MMP↓,
"highlight2" >Casp↑,
"highlight2" >selectivity↑, shikonin presented minimal toxicity to non-neoplastic colon cells and no liver injury in xenograft models
"highlight2" >cycD1↓, Cyclin D expression was decreased with shikonin treatment
"highlight2" >TumCCA↑, induced cell growth inhibition by the induction G1 cell cycle arrest.
"highlight2" >eff↓, NAC or GSH could block the shikonin-dependent burst of intracellular ROS

2361- SK,    Natural shikonin and acetyl-shikonin improve intestinal microbial and protein composition to alleviate colitis-associated colorectal cancer
- in-vivo, CRC, NA
"highlight2" >GutMicro↑, Both SK and acetyl-SK decreased AOM/DSS-induced CAC, and regulated the intestinal flora structure in CAC mouse model
"highlight2" >Dose↝, 20 mg/kg SK exhibited the most effective functions, even better than the positive drug mesalazine.
"highlight2" >IL1β↓, SK could recover the increase of pro-inflammatory cytokines (including IL-1β, IL-6 and TNF-α), the upregulation of pyruvate kinase isozyme type M2 (PKM2)
"highlight2" >IL6↓,
"highlight2" >TNF-α↓,
"highlight2" >PKM2↓,

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
"highlight2" >Apoptosis↑, shikonin induced cell apoptosis by down-regulating BCL-2 and activating caspase-3/9 and the cleavage of PARP.
"highlight2" >Bcl-2↓,
"highlight2" >Casp3↑,
"highlight2" >Casp9↑,
"highlight2" >cl‑PARP↑,
"highlight2" >GRP78/BiP↑, The expression of BiP and the PERK/elF2α/ATF4/CHOP and IRE1α /JNK signaling pathways were upregulated after shikonin treatment.
"highlight2" >PERK↑,
"highlight2" >eIF2α↑,
"highlight2" >ATF4↑,
"highlight2" >CHOP↑,
"highlight2" >JNK↑,
"highlight2" >eff↓, pre-treatment with N-acetyl cysteine significantly reduced the cytotoxicity of shikonin
"highlight2" >ER Stress↑, Shikonin induced endoplasmic reticulum stress
"highlight2" >ROS↑, Shikonin induced reactive oxygen species-mediated ER stress
"highlight2" >TumCG↓, Shikonin suppressed the growth of colorectal cancer cells in vivo

2227- SK,    Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species
- in-vitro, GC, BGC-823 - in-vitro, GC, SGC-7901 - in-vitro, Nor, GES-1
"highlight2" >selectivity↑, In vitro, SHK suppresses proliferation and triggers cell death of gastric cancer cells but leads minor damage to gastric epithelial cells.
"highlight2" >TumCP↓,
"highlight2" >TumCD↑,
"highlight2" >ROS↑, SHK induces the generation of intracellular reactive oxygen species (ROS), depolarizes the mitochondrial membrane potential (MMP) and ultimately triggers mitochondria-mediated apoptosis.
"highlight2" >MMP↓,
"highlight2" >Casp↑, SHK induces apoptosis of gastric cancer cells not only in a caspase-dependent manner which releases Cytochrome C and triggers the caspase cascade
"highlight2" >Cyt‑c↑,
"highlight2" >Endon↑, nuclear translocation of AIF and Endonuclease G
"highlight2" >AIF↑,
"highlight2" >eff↓, NAC and GSH significantly inhibited SHK-induced death
"highlight2" >ChemoSen↑, SHK enhances chemotherapeutic sensitivity of 5-fluorouracil and oxaliplatin
"highlight2" >TumCCA↑, SHK caused S-phase cell cycle arrest in SGC-7901 and BGC-823 gastric cancer cells
"highlight2" >GSH/GSSG↓, We found that the GSH/GSSG ratio was significantly decreased when treated with SHK.
"highlight2" >lipid-P↑, SHK increases lipid peroxidation and induces apoptosis in vivo

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
"highlight2" >selectivity↑, shikonin induced apoptosis of Huh7 and BEL7402 but not nontumorigenic cells.
"highlight2" >ROS↑, ROS generation was detected
"highlight2" >eff↓, ROS scavengers completely inhibited shikonin-induced apoptosis, indicating that ROS play an essential role
"highlight2" >Akt↓, downregulation of Akt and RIP1/NF-κB activity was found to be involved in shikonin-induced apoptosis
"highlight2" >RIP1↓,
"highlight2" >NF-kB↓,

2225- SK,    Shikonin protects skin cells against oxidative stress and cellular dysfunction induced by fine particulate matter
- in-vitro, Nor, HaCaT
"highlight2" >*antiOx↑, antioxidant capabilities of shikonin and its ability to protect human keratinocytes from oxidative stress induced by fine particulate matter
"highlight2" >*ROS↓, 3 µM was nontoxic to human keratinocytes and effectively scavenged reactive oxygen species (ROS) while increasing the production of reduced glutathione (GSH).
"highlight2" >*GSH↑,
"highlight2" >*GCLC↑, Shikonin increased the expression of GCLC and GSS via AKT and NRF2 activation
"highlight2" >*GSS↑,
"highlight2" >*Akt↑,
"highlight2" >*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
"highlight2" >PYCR1↓, SK may induce apoptosis and autophagy by reducing the expression of PYCR1 and suppressing PI3K/Akt/mTOR
"highlight2" >PI3K↓,
"highlight2" >Akt↓,
"highlight2" >mTOR↓,
"highlight2" >eff↑, SK reinforces its anti-tumor effects by downregulating PYCR1 in HCC cells

2223- SK,    Non-metabolic enzyme function of PKM2 in hepatocellular carcinoma: A review
- in-vitro, Var, NA
"highlight2" >PKM2↓, Many studies have found that shikonin can inhibit PKM2 expression in various tumors and is a classic PKM2 inhibitor

2222- SK,    The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis
- in-vitro, OS, U2OS - in-vitro, OS, 143B - in-vivo, NA, NA
"highlight2" >Necroptosis↑, Shikonin induced necroptosis in osteosarcoma cells
"highlight2" >RIP1↑, Shikonin induced necroptosis via upregulating RIP1 and RIP3
"highlight2" >RIP3↑,
"highlight2" >OS↑, Shikonin prolonged the survival of metastatic disease
"highlight2" >P53↑, protein level of p53 was increased after treated with shikonin for 8 hours

2221- SK,    Shikonin Induces Apoptosis, Necrosis, and Premature Senescence of Human A549 Lung Cancer Cells through Upregulation of p53 Expression
- in-vitro, Lung, A549
"highlight2" >Apoptosis↑, shikonin significantly induced cell apoptosis and reduced proliferation in a dose-dependent manner.
"highlight2" >TumCP↓,
"highlight2" >tumCV↓, shikonin (1–2.5 μg/mL) cause viability reduction
"highlight2" >Necroptosis↑, while higher concentrations (5–10 μg/mL) precipitate both apoptosis and necrosis.
"highlight2" >P53↑, via p53-mediated cell fate pathways
"highlight2" >ROS↑, Its cytotoxic actions are largely through enhancing ROS generation to trigger caspase-dependent apoptosis and to downregulate nuclear factor-kappa B- (NF-kB-) mediated matrix metalloproteinase (MMP) expressions to reduce tumor survival and invasion
"highlight2" >NF-kB↓,

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
"highlight2" >*RenoP↑, Shikonin significantly and dose-dependently alleviated gentamicin-induced renal injury, as revealed by restoring normal kidney function and histological architecture.
"highlight2" >*ROS↓, Shikonin Defended against Renal Oxidative Stress and Activated the SIRT1/Nrf2/HO-1 Cascades in Rats with Gentamicin-Induced Renal Damage
"highlight2" >*SIRT1↓,
"highlight2" >*NRF2↑,
"highlight2" >*HO-1↑,
"highlight2" >*GSH↑, significant rise in GSH, TAC levels, and SOD activity, as well as SIRT1, Nrf2, and HO-1 protein levels
"highlight2" >*TAC↑,
"highlight2" >*SOD↑,
"highlight2" >*MDA↓, significant decrease in the renal MDA, NO, and iNOS
"highlight2" >*NO↓,
"highlight2" >*iNOS↓,
"highlight2" >*NHE3↑, shikonin treatment significantly and dose-dependently enhanced the reduced NHE3 level and mRNA expression induced by repeated gentamicin injections,
"highlight2" >*PI3K↑, in the current study, shikonin treatment of the gentamicin-injected groups increased PI3K

2219- SK,    Shikonin induces apoptosis of HaCaT cells via the mitochondrial, Erk and Akt pathways
- in-vitro, Nor, HaCaT
"highlight2" >*MMP↓, Shikonin decreases the Δψm and induces ROS generation
"highlight2" >*ROS↑,
"highlight2" >*Casp3↑, shikonin significantly increased caspase 3 cleavage, as compared with the untreated cells
"highlight2" >*TumCG↓, Shikonin inhibits the growth of HaCaT cells

2218- SK,    Shikonin Alleviates Endothelial Cell Injury Induced by ox-LDL via AMPK/Nrf2/HO-1 Signaling Pathway
- in-vitro, Nor, HUVECs
"highlight2" >*Dose↝, When the shikonin concentration was >0.1 μmol/L, the cell viability increased significantly.
"highlight2" >*Apoptosis↓, SKN Reduces ox-LDL-Induced Endothelial Cell Apoptosis
"highlight2" >*Casp3↓, SKN pretreatment downregulated the cleaved caspase-3 protein levels and upregulated Bcl-2 protein levels in a concentration-dependent manner.
"highlight2" >*Bcl-2↑,
"highlight2" >*Inflam↓, SKN Downregulates the Expression of Inflammatory Factors Induced by ox-LDL
"highlight2" >*VCAM-1↓, SKN pretreatment significantly downregulates the levels of VCAM1, ICAM1, and E-selectin proteins.
"highlight2" >*ICAM-1↓,
"highlight2" >*E-sel↓,
"highlight2" >*ROS↓, SKN pretreatment significantly decreases the generation of ROS and increases the SOD activity induced by ox-LDL.
"highlight2" >*SOD↑,
"highlight2" >*AMPK↑, SKN Inhibits Oxidative Stress Damage by Activating the AMPK-Nrf2-HO-1 Pathway
"highlight2" >*NRF2↑,
"highlight2" >*HO-1↑,
"highlight2" >*TNF-α↓, TNF-α, IL-1β, IL-6, VCAM1, ICAM1, and E-selectin in endothelial cells, while SKN treatment significantly downregulated the expression of these proteins mentioned above
"highlight2" >*IL1β↓,
"highlight2" >*IL6↓,

2470- SK,    PKM2/PDK1 dual-targeted shikonin derivatives restore the sensitivity of EGFR-mutated NSCLC cells to gefitinib by remodeling glucose metabolism
- in-vitro, Lung, H1299
"highlight2" >PKM2↓, Base on this, we designed a series of novel shikonin (SK) thioether derivatives as PKM2/PDK1 dual-target agents, among which the most potent compound E5 featuring a 2-methyl substitution on the benzene ring exerted significantly increased inhibitory
"highlight2" >PDK1↓,
"highlight2" >Glycolysis↓, E5 could significantly inhibit the proliferation and aerobic glycolysis of NSCLC cell

3051- SK,    Resveratrol mediates its anti-cancer effects by Nrf2 signaling pathway activation
- Review, Var, NA
"highlight2" >Nrf1↑, Resveratrol is a natural compound that can activate the Nrf2 transcription factor
"highlight2" >Apoptosis↑, In different cell lines, resveratrol can increase apoptosis and inhibit the proliferation of cancer cells.
"highlight2" >TumCP↓,
"highlight2" >eff⇅, But there is a controversy on whether activation of Nrf2 is of clinical benefit in cancer therapy or is a carcinogen?
"highlight2" >chemoP↑, chemoprevention effects
"highlight2" >eff↑, It has also been suggested that reduction in oxidative conditions in cancer cells may enhance the anticancer effects of antineoplastic drugs [4].
"highlight2" >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
"highlight2" >Hif1a↓,

3050- SK,    Systemic administration of Shikonin ameliorates cognitive impairment and neuron damage in NPSLE mice
- in-vivo, Nor, NA
"highlight2" >*Inflam↓, Shikonin relieved the progression of NPSLE by suppressing neuroinflammation.
"highlight2" >*neuroP↑, Shikonin repaired the loss of neuronal synapses in NPSLE mice.
"highlight2" >*cognitive↑, Shikonin ameliorates cognitive impairment

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
"highlight2" >*neuroP↑, Shikonin (SK) exerts neuroprotective effects
"highlight2" >*p‑PTEN↓, SK administration reversed the upregulation of p-PTEN and the downregulation of p-Akt, p-CREB, and BDNF
"highlight2" >*p‑Akt↑,
"highlight2" >*Bcl-2↑, SK treatment upregulated the expression of bcl-2 and downregulated the expression of bax, thereby elevating the bcl-2/bax ratio.
"highlight2" >*BAX↓,
"highlight2" >*cognitive↑, , consequently improving cognitive impairment.
"highlight2" >*BDNF↑, Western blot analysis showed higher p-PTEN and lower p-Akt, p-CREB, and BDNF expression in the vehicle group than in the sham group.

3048- SK,    Shikonin inhibits triple-negative breast cancer-cell metastasis by reversing the epithelial-to-mesenchymal transition via glycogen synthase kinase 3β-regulated suppression of β-catenin signaling
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, 4T1 - in-vitro, Nor, MCF12A - in-vivo, NA, NA
"highlight2" >tumCV↓, results revealed that shikonin potently decreased the viabilities of TNBC MDA-MB-231 and 4T1 cells but showed less cytotoxicity to normal mammary epithelial MCF-12A cells
"highlight2" >selectivity↑,
"highlight2" >EMT↓, shikonin reversed the epithelial-to-mesenchymal transition (EMT) in MDA-MB-231 and 4T1 cells.
"highlight2" >TumCMig↓, Shikonin depressed cell migration and invasion, upregulated E-cadherin levels, downregulated N-cadherin, vimentin, and Snail levels, and reorganized the cytoskeletal proteins F-actin and vimentin.
"highlight2" >TumCI↓,
"highlight2" >E-cadherin↑,
"highlight2" >N-cadherin↓,
"highlight2" >Vim↓,
"highlight2" >Snail↓,
"highlight2" >β-catenin/ZEB1↓, Shikonin reversed EMT by inhibiting activation of β-catenin signaling through attenuating β-catenin expression
"highlight2" >GSK‐3β↑, shikonin upregulated glycogen synthase kinase 3β (GSK-3β) levels, leading to enhanced phosphorylation and decreased levels of β-catenin.

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
"highlight2" >TumCG↓, SKN inhibited colon cancer cell growth, suppressed both constitutive and IL-6-induced STAT3 phosphorylation, and downregulated the expression of ADAM17
"highlight2" >p‑STAT3↓,
"highlight2" >ADAM17↓,
"highlight2" >Apoptosis↑, SKN promoted cell apoptosis, as evidenced by increased expression levels of cleaved caspase-3 and cleaved PARP in both cell lines
"highlight2" >Casp3↑,
"highlight2" >cl‑PARP↑,
"highlight2" >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
"highlight2" >cycE↓,
"highlight2" >TumCCA↑,
"highlight2" >JAK1?, The inhibitory effects of SKN on the phosphorylation of both JAK1 and JAK2 in the two cell lines were also observed
"highlight2" >p‑JAK1↓,
"highlight2" >p‑JAK2↓,
"highlight2" >p‑eIF2α↑, phosphorylation levels of eIF2α were enhanced by SKN (20 µM) in the HCT116 and SW480 colon cancer cells
"highlight2" >eff↓, NAC decreased SKN-induced p-eIF2α expression and reversed the SKN-mediated downregulation of ADAM17 protein expression
"highlight2" >ROS↑, suppressed the expression of ADAM17 mediated by ROS-associated p-eIF2α expression in the HCT116 and SW480 colon cancer cells
"highlight2" >IL6↓, demonstrated that the antitumor effects of SKN on colon cancer cells were associated with its inhibition of the IL-6/STAT3 signaling pathway.

3046- SK,    Shikonin attenuates lung cancer cell adhesion to extracellular matrix and metastasis by inhibiting integrin β1 expression and the ERK1/2 signaling pathway
- in-vitro, Lung, A549
"highlight2" >TumCP↓, A549 cells were treated with shikonin for 24 h, 8.0 μM shikonin significantly inhibited cell proliferation,
"highlight2" >TumCI↓, while cells treated with less than 2.0 μM shikonin for 24 h significantly suppressed cell adhesion to the ECM, invasion and migration in a dose-dependent manner.
"highlight2" >TumCMig↓,
"highlight2" >p‑ERK↓, shikonin repressed the phosphorylation of extracellular signal-regulated kinase (ERK1/2
"highlight2" >ITGB1↓, shikonin suppresses lung cancer invasion and metastasis by inhibiting integrin β1 expression and the ERK1/2 signaling pathway.

3045- SK,    Cutting off the fuel supply to calcium pumps in pancreatic cancer cells: role of pyruvate kinase-M2 (PKM2)
- in-vitro, PC, MIA PaCa-2
"highlight2" >ECAR↓, Shikonin caused a concentration- and time-dependent inhibition of ECAR, which was more effective in highly glycolytic cells cultured in high-glucose (25 mM, Fig. 3ci) vs glucose-restricted cells (5 mM, Fig. 3cii).
"highlight2" >Glycolysis↓, Collectively, these data suggest that shikonin exerts its cytotoxicity by inhibiting glycolysis and inducing ATP depletion, most likely due to inhibition of PKM2.
"highlight2" >ATP↓, Only the highest concentration of shikonin (5 µM) induced a significant ATP depletion between 15 min and 6 h
"highlight2" >PKM2↓,
"highlight2" >TumCMig↓, Shikonin reduces PDAC cell migration
"highlight2" >Ca+2↑, Shikonin induces cytotoxic Ca2+ overload
"highlight2" >GlucoseCon↓, shikonin inhibited glucose consumption and lactate production with an IC50 of 5–10 μM in MCF-7 cells that exclusively express PKM2
"highlight2" >lactateProd↓,
"highlight2" >MMP↓, Shikonin is also reported to impair mitochondrial function and increase oxidative stress
"highlight2" >ROS↑,

3044- SK,    Shikonin Inhibits Non-Small-Cell Lung Cancer H1299 Cell Growth through Survivin Signaling Pathway
- in-vitro, Lung, H1299 - in-vitro, Lung, H460
"highlight2" >TumCP↓, Results showed that shikonin inhibited the NSCLC H1299 cell proliferation in a dose-dependent manner.
"highlight2" >survivin↓, Shikonin also inhibited the mRNA expression and protein level of survivin in H1299 cells
"highlight2" >TumCCA↓, Shikonin arrested H1299 cell cycle at the G0/G1 phase by regulating CDK/cyclin family members
"highlight2" >CDK2↓,
"highlight2" >CDK4↓,
"highlight2" >XIAP↓, shikonin regulated the expression of X-linked inhibitor of apoptosis- (XIAP-) mediated caspases 3 and 9, thus leading to the damage of mitochondrial membrane potential and induction of H1299 cell apoptosis.
"highlight2" >Casp3↑, subsequently regulates the protein expression of XIAP/caspase 3/9, CDK2/4, and cyclin E/D1.
"highlight2" >Casp9↑,
"highlight2" >cycD1↓, downregulated the protein levels of CDK2, CDK4, cyclin E, and cyclin D1
"highlight2" >cycE↓,

3043- SK,    Shikonin Induces Apoptosis by Inhibiting Phosphorylation of IGF-1 Receptor in Myeloma Cells.
- in-vitro, Melanoma, RPMI-8226
"highlight2" >IGF-1↓, Shikonin Induces Apoptosis by Inhibiting Phosphorylation of IGF-1 Receptor in Myeloma Cells
"highlight2" >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.
"highlight2" >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
"highlight2" >MMP↓, Shikonin-induced apoptosis was in association with the loss of mitochondrial transmembrane potentials, and activation of caspase-3.
"highlight2" >Casp3↑,
"highlight2" >P53↑, Expression of p53 and Bax proteins was increased with down-regulation of Mcl-1 protein
"highlight2" >BAX↑,
"highlight2" >Mcl-1↓,
"highlight2" >EGFR↓, Shikonin has reported to be an inhibitor of protein tyrosine kinase such as EGFR, v-Src, and KDR/Flk-1.
"highlight2" >Src↑,
"highlight2" >KDR/FLK-1↓,
"highlight2" >p‑IGF-1↓, Shikonin inhibited phosphorylation of IGF-1 receptor as early as 30 min with inhibition of PI3K/Akt signaling
"highlight2" >PI3K↓,
"highlight2" >Akt↓,

3042- SK,    The protective effects of Shikonin on lipopolysaccharide/D -galactosamine-induced acute liver injury via inhibiting MAPK and NF-kB and activating Nrf2/HO-1 signaling pathways
- in-vivo, Nor, NA
"highlight2" >*TNF-α↓, Our results showed that SHK treatment distinctly decreased serum TNF-a, IL-1b, IL-6 and IFN-g inflammatory cytokine production
"highlight2" >*IL1β↓,
"highlight2" >*IL6↓,
"highlight2" >*IFN-γ↓,
"highlight2" >*ALAT↓, , reduced serum ALT, AST, hepatic MPO and ROS production levels,
"highlight2" >*AST↓,
"highlight2" >*MPO↓,
"highlight2" >*ROS↓,
"highlight2" >*JNK↓, inhibited JNK1/2, ERK1/2, p38 and NF-kB (p65) phosphorylation, and suppressed IkBa phosphorylation and degradation.
"highlight2" >*ERK↓,
"highlight2" >*p38↓,
"highlight2" >*NF-kB↓,
"highlight2" >*p‑IKKα↓,
"highlight2" >*SOD↑, SHK could dramatically increase SOD and GSH production, as well as reduce ROS production,
"highlight2" >*GSH↑,
"highlight2" >*HO-1↑, through up-regulating the protein expression of HO-1, Nqo1, Gclc and Gclm, which was related to the induction of Nrf2 nuclear translocation.
"highlight2" >*NRF2↑,
"highlight2" >*hepatoP↑,

3041- SK,    Promising Nanomedicines of Shikonin for Cancer Therapy
- Review, Var, NA
"highlight2" >Glycolysis↓, SHK could regulate immunosuppressive tumor microenvironment through inhibiting glycolysis of tumor cells and repolarizing tumor-associated macrophages (TAMs).
"highlight2" >TAMS↝,
"highlight2" >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.
"highlight2" >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.
"highlight2" >P21↑, Table 1
"highlight2" >ERK↓,
"highlight2" >ROS↑,
"highlight2" >GSH↓,
"highlight2" >MMP↓,
"highlight2" >TrxR↓,
"highlight2" >MMP13↓,
"highlight2" >MMP2↓,
"highlight2" >MMP9↓,
"highlight2" >SIRT2↑,
"highlight2" >Hif1a↓,
"highlight2" >PKM2↓,
"highlight2" >TumCP↓, Inhibit Cell Proliferation
"highlight2" >TumMeta↓, Inhibit Cells Metastasis and Invasion
"highlight2" >TumCI↓,

3040- SK,    Pharmacological Properties of Shikonin – A Review of Literature since 2002
- Review, Var, NA - Review, IBD, NA - Review, Stroke, NA
"highlight2" >*Half-Life↝, One study using H-shikonin in mice showed that shikonin was rapidly absorbed after oral and intramuscular administration, with a half-life in plasma of 8.79 h and a distribution volume of 8.91 L/kg.
"highlight2" >*BioAv↓, shikonin is generally used in creams and ointments, that is, oil-based preparations; indeed, its insolubility in water is usually the cause of its low bioavailability
"highlight2" >*BioAv↑, 200-fold increase in the solubility, photostability, and in vitro permeability of shikonin through the formation of a 1 : 1 inclusion complex with hydroxypropyl-β-cyclodextrin.
"highlight2" >*BioAv↑, 181-fold increase in the solubility of shikonin in aqueous media in the presence of β-lactoglobulin at a concentra- tion of 3.1 mg/mL
"highlight2" >*Inflam↓, anti-inflammatory effect of shikonin
"highlight2" >*TNF-α↓, shikonin inhibited TNF-α production in LPS-stimulated rat primary macrophages as well as NF-κB translocation from the cytoplasm to the nucleus.
"highlight2" >*other↑, authors found that treatment with shikonin prevented the shortening of the colorectum and decreased weight loss by 5 % while improving the ap- pearance of feces and preventing bloody stools.
"highlight2" >*MPO↓, MPO activity was reduced as well as the expression of COX-2, the activation of NF-κB and that of STAT3.
"highlight2" >*COX2↓,
"highlight2" >*NF-kB↑,
"highlight2" >*STAT3↑,
"highlight2" >*antiOx↑, Antioxidant Effects of Shikonin
"highlight2" >*ROS↓, radical scavenging activity of shikonin
"highlight2" >*neuroP↑, shown to exhibit a neuroprotective effect against the damage caused by ischemia/reperfusion in adult male Kunming mice
"highlight2" >*SOD↑, it also attenuated neuronal damage and the upregulation of superoxide dismutase, catalase, and glutathione peroxidase activities while reducing the glutathione/glutathione disulfide ratio.
"highlight2" >*Catalase↑,
"highlight2" >*GPx↑,
"highlight2" >*Bcl-2↑, shikonin upregulated Bcl-2, downregulated Bax and prevented cell nuclei from undergoing morphological changes typical of apoptosis.
"highlight2" >*BAX↓,
"highlight2" >cardioP↑, Two different studies have suggested a possible cardioprotective effect of shikonin that would be related to its anti-inflammatory and antioxidant effects.
"highlight2" >AntiCan↑, A wide spectrum of anticancer mechanisms of action have been described for shikonin:
"highlight2" >NF-kB↓, suppression of NF-κB-regulated gene products [44],
"highlight2" >ROS↑, ROS generation [46],
"highlight2" >PKM2↓, inhibition of tumor-specific pyruvate kinase-M2 [47,48]
"highlight2" >TumCCA↑, cell cycle arrest [49]
"highlight2" >Necroptosis↑, or induction of necroptosis [50],
"highlight2" >Apoptosis↑, shikonin at 1 μM induced caspase-dependent apoptosis in U937 cells after 6 h with an increase in DNA fragmentation, intracellular ROS, low mitochondrial membrane potential
"highlight2" >DNAdam↑,
"highlight2" >MMP↓,
"highlight2" >Cyt‑c↑, At 10 μM, shikonin induced a greater release of cytochrome c from the mitochondria and of lactate dehydrogenase,
"highlight2" >LDH↝,

2217- SK,    Shikonin Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis to Attenuate Renal Ischemia/Reperfusion Injury by Activating the Sirt1/Nrf2/HO-1 Pathway
- in-vivo, Nor, NA - in-vitro, Nor, HK-2
"highlight2" >*ER Stress↓, shikonin alleviated ER stress-induced apoptosis in I/R mice
"highlight2" >*SIRT1↑, shikonin activated Sirt1/Nrf2/HO-1 signaling post-I/R
"highlight2" >*NRF2↑,
"highlight2" >*HO-1↑,
"highlight2" >*eff↓, inhibition of Sirt1 limited shikonin-mediated protection against ER stress-stimulated apoptosis in both animal and cellular models.
"highlight2" >*RenoP↑, Shikonin pretreatment alleviates renal I/R injury through activating Sirt1/Nrf2/HO-1 signaling to inhibit ER stress-mediated apoptosis.
"highlight2" >*GRP78/BiP↓, The current study revealed that shikonin significantly downregulated GRP78, CHOP, caspase-12, Bax, and cleaved caspase-3 proteins levels in renal tissues of I/R mice and H/R-challenged HK-2 cells
"highlight2" >*CHOP↓,
"highlight2" >*Casp12↓,
"highlight2" >*BAX↓,
"highlight2" >*cl‑Casp3↓,

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
"highlight2" >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
"highlight2" >Pyro↑,
"highlight2" >Casp↑,
"highlight2" >cl‑PARP↑,
"highlight2" >GSDME↑,
"highlight2" >ROS↑,
"highlight2" >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
"highlight2" >PDK1↓,
"highlight2" >Akt↓,
"highlight2" >ERK↓,
"highlight2" >eff↓, Notably, COX-2 overexpression attenuated shikonin-induced apoptosis and pyroptosis
"highlight2" >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
"highlight2" >eff↑, Celecoxib augmented the cytotoxic effects of shikonin by promoting the apoptosis and pyroptosis of H1975 cells

2420- SK,    Pyruvate kinase M2 regulates mitochondrial homeostasis in cisplatin-induced acute kidney injury
- in-vivo, AKI, NA
"highlight2" >PKM2↓, Shikonin is a naphthoquinone compound extracted from the roots of Chinese traditional medicine and has been identified as a new PKM2 inhibitor that prevents glycolysis in cancer cells
"highlight2" >other↝, In our study, we demonstrate that PKM2 translocates into mitochondria in renal tubular epithelial cells during AKI induced by cisplatin.

2419- SK,    Regulation of glycolysis and the Warburg effect in wound healing
- in-vivo, Nor, NA
"highlight2" >Glycolysis↓, Treatment with 5–10 μM of the glycolysis inhibitor shikonin significantly decreased gene expression of the facilitative glucose transporters, GLUT1 and GLUT3
"highlight2" >GLUT1↓,
"highlight2" >GLUT3↓,
"highlight2" >HK2↓, shikonin downregulated expression of the rate-limiting enzymes HK1 and HK2, although a 20 μM dose was needed
"highlight2" >HK1↓, HK1
"highlight2" >PFK1↓, Shikonin treatment also downregulated the rate-limiting enzyme PFK1
"highlight2" >PFK2↓, PFK2 expression was only significantly lowered with a 20 μM dose
"highlight2" >PKM2↓, 5 μM shikonin treatment inhibits gene expression of PKM2 (8.59 vs. 2.30, P < 0.001) and downregulated PDK1
"highlight2" >lactateProd↓, coupled with decreased lactate production at higher concentrations of shikonin (10 μM and 20 μM)
"highlight2" >GlucoseCon↓, shikonin effectively downregulated key enzymes involved in glucose uptake, glycolysis, and lactate production

2418- SK,    Experimental Study of Hepatocellular Carcinoma Treatment by Shikonin Through Regulating PKM2
- in-vitro, HCC, SMMC-7721 cell - in-vitro, HCC, HUH7 - in-vitro, HCC, HepG2
"highlight2" >tumCV↓, The results of CCK-8 showed that shikonin significantly inhibited cell viability of HCC cells.
"highlight2" >GlucoseCon↓, The levels of glucose uptake and lactate production were dramatically decreased by shikonin-treated.
"highlight2" >lactateProd↓,
"highlight2" >ChemoSen↑, shikonin enhanced the anti-cancer effect of sorafenib in vitro and in vivo.
"highlight2" >PKM2↓, By inhibiting PKM2, shikonin inhibited proliferation and glycolysis and induced cell apoptosis in HCC cells.
"highlight2" >Glycolysis↓,

2417- SK,    Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer
- in-vitro, Lung, A549 - in-vitro, Lung, H446
"highlight2" >TumCP↓, Shikonin treatment decreased the proliferation, migration, invasion, glucose uptake, lactate levels, ATP levels and PFKFB2 expression levels and increased apoptosis in lung cancer cells in a dose‑dependent manner.
"highlight2" >TumCMig↓,
"highlight2" >TumCI↓,
"highlight2" >GlucoseCon↓,
"highlight2" >lactateProd↓,
"highlight2" >PFKFB2↓,
"highlight2" >Warburg↓, shikonin inhibited the Warburg effect and exerted antitumor activity in lung cancer cells, which was associated with the downregulation of PFKFB2 expression.
"highlight2" >GLUT1∅, while the expression levels of the other proteins (PDK1, GLUT1, PGK2, LDHA, PKM2, GLUT3, PDH and p-PDH) were not altered by shikonin treatment.
"highlight2" >LDHA∅,
"highlight2" >PKM2∅,
"highlight2" >GLUT3∅,
"highlight2" >PDH∅,

2416- SK,    Shikonin induces cell death by inhibiting glycolysis in human testicular cancer I-10 and seminoma TCAM-2 cells
- in-vitro, Testi, TCAM-2
"highlight2" >MMP↓, Shikonin treatment significantly reduced mitochondrial membrane potential, increased ROS levels and lower the level of lactic acid in both I-10 and TCAM-2 cells
"highlight2" >ROS↑,
"highlight2" >lactateProd↓,
"highlight2" >Bcl-2↓, shikonin treatment significantly down- regulated the expressions of Bax, Bcl-2, cleaved caspase-3, PKM2, GLUT1 and HK2, and up-regulated the expression of autophagy-related protein LC3B
"highlight2" >cl‑Casp3↓,
"highlight2" >PKM2↓,
"highlight2" >GLUT1↓,
"highlight2" >HK2↓,
"highlight2" >LC3B↑,

2415- SK,    Shikonin induces programmed death of fibroblast synovial cells in rheumatoid arthritis by inhibiting energy pathways
- in-vivo, Arthritis, NA
"highlight2" >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.
"highlight2" >TumAuto↑,
"highlight2" >ROS↑,
"highlight2" >ATP↓,
"highlight2" >Glycolysis↓, shikonin can inhibit RA-glycolysis in FLSs
"highlight2" >PI3K↓,
"highlight2" >Akt↓,
"highlight2" >mTOR↓,
"highlight2" >*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
"highlight2" >*Inflam↓,
"highlight2" >*TNF-α↓,
"highlight2" >*IL6↓,
"highlight2" >*IL8↓,
"highlight2" >*IL10↓,
"highlight2" >*IL17↓,
"highlight2" >*hepatoP↑, while showing less toxicity to the liver and kidney.
"highlight2" >*RenoP↑,
"highlight2" >PKM2↓, The expression of glycogen proteins PKM2, GLUT1, and HK2 decreased with increasing concentrations of shikonin
"highlight2" >GLUT1↓,
"highlight2" >HK2↓,

2370- SK,    The role of pyruvate kinase M2 in anticancer therapeutic treatments
- Review, Var, NA
"highlight2" >Glycolysis↓, In summary, shikonin is able to inhibit tumor growth by suppressing aerobic glycolysis, which is mediated by PKM2 in vivo
"highlight2" >PKM2↓,
"highlight2" >EGFR↓, another study indicated that shikonin reduced epidermal growth factor receptor, PI3K, p-AKT, Hypoxia inducible factor-1α (HIF-1α) and PKM2 expression levels
"highlight2" >PI3K↓,
"highlight2" >p‑Akt↓,
"highlight2" >Hif1a↓,

2364- SK,    Pyruvate Kinase M2 Mediates Glycolysis Contributes to Psoriasis by Promoting Keratinocyte Proliferation
- in-vivo, PSA, NA
"highlight2" >eff↑, Shikonin or 2-DG treatment significantly attenuated the severity of skin lesions in animals
"highlight2" >lactateProd↓, Lactate measurement showed decreased serum lactate levels in the Shikonin or 2-DG treatment IMQ-induced mice, compared with that in the IMQ treatment group
"highlight2" >PKM2↓, results suggested that PKM2 inhibition may be an important approach for psoriasis treatment.

2363- SK,    Inhibition of PKM2 by shikonin impedes TGF-β1 expression by repressing histone lactylation to alleviate renal fibrosis
- in-vivo, CKD, NA
"highlight2" >PKM2↓, In UUO mice, treatment with shikonin, a potent PKM2 inhibitor, effectively reduced lactate production, alleviated renal fibrosis, decreased TGF-β1 expression, and suppressed the MMT process.
"highlight2" >lactateProd↓,
"highlight2" >TGF-β↓,

2362- SK,    RIP1 and RIP3 contribute to shikonin-induced glycolysis suppression in glioma cells via increase of intracellular hydrogen peroxide
- in-vitro, GBM, U87MG - in-vivo, GBM, NA - in-vitro, GBM, U251
"highlight2" >RIP1↑, we found shikonin activated RIP1 and RIP3 in glioma cells in vitro and in vivo, which was accompanied with glycolysis suppression
"highlight2" >RIP3↑,
"highlight2" >Glycolysis↓,
"highlight2" >G6PD↓, shikonin-induced decreases of glucose-6-phosphate and pyruvate and downregulation of HK II and PKM2
"highlight2" >HK2↓,
"highlight2" >PKM2↓,
"highlight2" >H2O2↑, shikonin also triggered accumulation of intracellular H2O2 and depletion of GSH and cysteine
"highlight2" >GSH↓,
"highlight2" >ROS↑, It was documented that inhibition of HK II with its inhibitor 3-bromopyruvate or knockdown of its level resulted in accumulation of ROS

1345- SK,    The Critical Role of Redox Homeostasis in Shikonin-Induced HL-60 Cell Differentiation via Unique Modulation of the Nrf2/ARE Pathway
- in-vitro, AML, HL-60
"highlight2" >CD14↑,
"highlight2" >CD11b↑,
"highlight2" >ROS↑, Shikonin result in the predominance of cell death because the oxidative stress is more severe and overcome the antioxidative capacity of Nrf2/ARE pathway, resulting in cell death.
"highlight2" >GSH↓,
"highlight2" >GSH/GSSG↓,
"highlight2" >GPx↑, mRNA expression levels of GPX and CAT were markedly upregulated by Shikonin in a dose-dependent manner
"highlight2" >Catalase↓, Shikonin causes apoptosis in human glioma cells by interrupting intracellular redox homeostasis, which included CAT downregulation
"highlight2" >Diff↑, Shikonin-induced HL-60 cell differentiation

2186- SK,    Shikonin differentially regulates glucose metabolism via PKM2 and HIF1α to overcome apoptosis in a refractory HCC cell line
- in-vitro, HCC, HepG2 - in-vitro, HCC, HCCLM3
"highlight2" >Glycolysis↓, shikonin treatment has been reported to inhibit glycolysis by suppressing the activity of pyruvate kinase M2 (PKM2) and to induce apoptosis by increasing reactive oxygen species (ROS) production.
"highlight2" >PKM2↓,
"highlight2" >Apoptosis↑,
"highlight2" >ROS↑,
"highlight2" >OXPHOS⇅, Shikonin up-regulated mitochondrial biogenesis to increase mitochondrial oxidative phosphorylation in HepG2 cells, but displayed the opposite trend in HCCLM3 cells.
"highlight2" >eff↓, insensitivity of HCCLM3 cells to shikonin treatment.

2185- SK,    Shikonin Inhibits Tumor Growth in Mice by Suppressing Pyruvate Kinase M2-mediated Aerobic Glycolysis
- in-vitro, Lung, LLC1 - in-vitro, Melanoma, B16-BL6 - in-vivo, NA, NA
"highlight2" >Glycolysis↓, confirming the inhibitory effect of shikonin on tumor aerobic glycolysis
"highlight2" >GlucoseCon↓, shikonin dose-dependently inhibited glucose uptake and lactate production in Lewis lung carcinoma (LLC) and B16 melanoma cells
"highlight2" >lactateProd↓,
"highlight2" >PKM2↓, suppression of cell aerobic glycolysis by shikonin is through decreasing PKM2 activity
"highlight2" >selectivity↑, shikonin treatment significantly promoted tumor cell apoptosis compared to untreated control cells.
"highlight2" >Warburg↓, agreement with previous findings of shikonin as a Warburg effect inhibitor
"highlight2" >TumVol↓, A significant reduction of tumor size (Fig. 7B) and weight (Fig. 7C) was observed when shikonin was injected at concentration of 1 or 10 mg/kg.
"highlight2" >TumW↓,

2184- SK,  Cisplatin,    PKM2 Inhibitor Shikonin Overcomes the Cisplatin Resistance in Bladder Cancer by Inducing Necroptosis
- in-vitro, CRC, T24
"highlight2" >PKM2↓, Down-regulation of PKM2 by siRNA or inhibition of PKM2 by shikonin re-sensitized the cisplatin resistant T24 cells.
"highlight2" >ChemoSen↑,
"highlight2" >Necroptosis↑, shikonin kills the T24 cisplatin resistant cells by inducing necroptosis

2183- SK,    Shikonin Inhibites Migration and Invasion of Thyroid Cancer Cells by Downregulating DNMT1
- in-vitro, Thyroid, TPC-1
"highlight2" >TumCMig↓, Shikonin inhibited TPC-1 cell migration and invasion in a dose-dependent manner
"highlight2" >TumCI↓,
"highlight2" >PTEN↑, The methylation of PTEN was suppressed by shikonin (increased the expression of PTEN)
"highlight2" >DNMT1↓, which also reduced the expression of DNMT1

2182- SK,  Cisplatin,    Shikonin inhibited glycolysis and sensitized cisplatin treatment in non-small cell lung cancer cells via the exosomal pyruvate kinase M2 pathway
- in-vitro, Lung, A549 - in-vitro, Lung, PC9 - in-vivo, NA, NA
"highlight2" >tumCV↓, shikonin inhibited the viability, proliferation, invasion, and migration of NSCLC cells A549 and PC9, and induced apoptosis.
"highlight2" >TumCP↓,
"highlight2" >TumCI↓,
"highlight2" >TumCMig↓,
"highlight2" >Apoptosis↑,
"highlight2" >PKM2↓, As the inhibitor of pyruvate kinase M2 (PKM2), a key enzyme in glycolysis, shikonin inhibited glucose uptake and the production of lactate
"highlight2" >Glycolysis↓,
"highlight2" >GlucoseCon↓,
"highlight2" >lactateProd↓,
"highlight2" >ChemoSen↑, In vivo chemotherapeutic assay showed that shikonin reduced the tumor volume and weight in NSCLC mice model and increased the sensitivity to cisplatin chemotherapy.
"highlight2" >TumVol↓,
"highlight2" >TumW↓,
"highlight2" >GLUT1↓, combination of shikonin and cisplatin downregulated the expression of PKM2 and its transcriptionally regulated downstream gene glucose transporter 1 (Glut1) in tumor tissue

2181- SK,    Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2
- in-vitro, BC, MCF-7 - in-vitro, Lung, A549 - in-vitro, Cerv, HeLa
"highlight2" >Glycolysis↓, Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines
"highlight2" >lactateProd↓,
"highlight2" >GlucoseCon↓,
"highlight2" >PKM2↓, shikonin and alkannin are the most potent and specific inhibitors to PKM2 reported so far
"highlight2" >LDH∅, LDH was not inhibited by shikonin, alkannin and the analogs

2011- SK,    Shikonin Attenuates Acetaminophen-Induced Hepatotoxicity by Upregulation of Nrf2 through Akt/GSK3β Signaling
- in-vitro, Nor, HL7702 - in-vivo, Nor, NA
"highlight2" >*NRF2↑, Shikonin (SHK) enhances Nrf2 in multiple lines of normal cells.
"highlight2" >*hepatoP↑, SHK defended APAP-induced liver toxicity, as well as reversed the levels of serum alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, and reactive oxygen species (ROS), while it enhanced the liver glutathione (GSH) le
"highlight2" >*ALAT↓, reversed the levels of serum alanine/aspartate aminotransferases (ALT/AST)
"highlight2" >*AST↓,
"highlight2" >*MPO↓,
"highlight2" >*ROS↓, neutralized oxidative stress in APAP-treated human normal liver L-02 cells
"highlight2" >*GSH↑, enhanced the liver glutathione (GSH) level in APAP-treated mice

2010- SK,    Shikonin inhibits gefitinib-resistant non-small cell lung cancer by inhibiting TrxR and activating the EGFR proteasomal degradation pathway
- in-vitro, Lung, H1975 - in-vitro, Lung, H1650 - in-vitro, Nor, CCD19
"highlight2" >EGFR↓, Shikonin is a potent inhibitor of EGFR
"highlight2" >selectivity↑, Shikonin exhibited selective cytotoxicity among two NSCLC cell lines (H1975 and H1650) and one normal lung fibroblast cell line (CCD-19LU).
"highlight2" >Casp↑, Shikonin significantly increased the activity of caspases and poly (ADP-ribosyl) polymerase (PARP), which are indicators of apoptosis
"highlight2" >PARP↑,
"highlight2" >Apoptosis↑,
"highlight2" >ROS↑, intensity of ROS by greater than 10-fold
"highlight2" >eff↓, NAC, an inhibitor of ROS, completely blocked apoptosis, caspase and PARP activation induced by Shikonin.
"highlight2" >selectivity↑, the IC50 value of Shikonin in CCD19 (normal cells) is approximately 4-fold higher than that of HCC827, H1650 and H1975.

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
"highlight2" >TumCG↓, shikonin has a selective inhibitory effect on bladder cancer cells
"highlight2" >selectivity↑, and has no toxicity on normal bladder epithelial cells
"highlight2" >*toxicity∅,
"highlight2" >Necroptosis↑, shikonin induced necroptosis and impaired autophagic flux via ROS generation
"highlight2" >ROS↑,
"highlight2" >p62↑, accumulation of autophagic biomarker p62 elevated p62/Keap1 complex and activated the Nrf2 signaling pathway to fight against ROS
"highlight2" >Keap1↑,
"highlight2" >*NRF2↑, activated the Nrf2 signaling pathway to fight against ROS
"highlight2" >eff↑, we further combined shikonin with late autophagy inhibitor(chloroquine) to treat bladder cancer and achieved a better inhibitory effect.

2008- SK,  Cisplatin,    Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo
- in-vitro, CRC, HCT116 - in-vivo, NA, NA
"highlight2" >ChemoSen↑, combination of shikonin and cisplatin exhibited synergistic anticancer efficacy
"highlight2" >selectivity↑, and achieved greater selectivity between cancer cells and normal cells.
"highlight2" >i-ROS↑, By inducing intracellular oxidative stress, shikonin potentiated cisplatin-induced DNA damage, followed by increased activation of mitochondrial pathway.
"highlight2" >DNAdam↑,
"highlight2" >MMP↓,
"highlight2" >TumCCA↑, induction of G2/M cell cycle arrest
"highlight2" >eff↓, NAC and GSH were used in our experiment. The MTT results revealed that scavenging of ROS fully attenuated combined treatment-induced cell growth inhibition against HCT116 cell
"highlight2" >*toxicity↓, combined treatment showed less cytotoxicity toward NCM460 normal human colon mucosal epithelial cells

2007- SK,    Shikonin Directly Targets Mitochondria and Causes Mitochondrial Dysfunction in Cancer Cells
- in-vitro, lymphoma, U937 - in-vitro, BC, MCF-7 - in-vitro, BC, SkBr3 - in-vitro, CRC, HCT116 - in-vitro, OS, U2OS - NA, Nor, RPE-1
"highlight2" >tumCV↓, We found that shikonin has strong cytotoxic effects on 15 cancer cell lines, including multidrug-resistant cell lines.
"highlight2" >selectivity↑, structure of mitochondria show marked differences between cancer cells and normal cells
"highlight2" >Dose↝, Shikonin inhibited proliferation by 50% in nearly all cancer cell lines at concentrations below 10 μM after 24 h.
"highlight2" >other↑, mitochondrion itself is a possible target of the compound
"highlight2" >MMP↓, Breakdown of the Mitochondrial Membrane Potential
"highlight2" >ROS↑, ROS production shortly after cellular shikonin uptake, and ROS levels continuously increased for at least 1 h after exposure to shikonin
"highlight2" >DNAdam↑, Induction of ROS, oxidative DNA damage, and elevated intracellular Ca2+ levels by shikonin
"highlight2" >Ca+2↑,
"highlight2" >Casp9↑, Caspase 9 is activated after the release of cytochrome c from the mitochondria
"highlight2" >Cyt‑c↑,
"highlight2" >*toxicity↓, RPE-1-GFP-EB3 (normal) cells were treated with 25 μM shikonin. shikonin treatment did cause a strong slowdown and finally a complete disappearance of EB3 particles within 3 min of application

1346- SK,    An Oxidative Stress Mechanism of Shikonin in Human Glioma Cells
- in-vitro, GBM, U87MG - in-vitro, GBM, Hs683
"highlight2" >NRF2↓, ROS production by shikonin resulted in the inhibition of nuclear translocation of Nrf2
"highlight2" >ROS↑, ROS generation from mitochondrial complex II
"highlight2" >Apoptosis↑,
"highlight2" >Cyt‑c↑, release cytochrome c to the cytosol
"highlight2" >GSH↓,
"highlight2" >MMP↓,
"highlight2" >P53↑,
"highlight2" >HO-1⇅, In Hs683 cells, the expressions of γ-GCS and HO-1 were slightly inhibited by shikonin at 3 h. However, shikonin increased the expressions of γ-GCS, catalase, SOD-1 and HO-1 at 24 h.

2187- SK,  VitK3,    Shikonin, vitamin K3 and vitamin K5 inhibit multiple glycolytic enzymes in MCF-7 cells
- in-vitro, BC, MCF-7
"highlight2" >Glycolysis↓, naphthaquinones, including shikonin, vitamin K3 and vitamin K5, have been proven to decrease the rate of glycolysis in cancer cells, which is partly due to suppressed pyruvate kinase activity.
"highlight2" >PKM2↓,

1344- SK,    Novel multiple apoptotic mechanism of shikonin in human glioma cells
- in-vitro, GBM, U87MG - in-vitro, GBM, Hs683 - in-vitro, GBM, M059K
"highlight2" >ROS↑,
"highlight2" >GSH↓,
"highlight2" >MMP↓,
"highlight2" >P53↑, upregulation of p53,
"highlight2" >cl‑PARP↑,
"highlight2" >Catalase↓,
"highlight2" >SOD1↑,
"highlight2" >Bcl-2↓,
"highlight2" >BAX↑,
"highlight2" >eff↓, Pretreatment with NAC, PFT-α, or cyclosporin A causes the recovery of shikonin-induced apoptosis.

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
"highlight2" >*BioAv↓, clinical use is limited by poor tumor targeting and low bioavailability
"highlight2" >ROS↑,
"highlight2" >GSH↓,
"highlight2" >TumCG↓,

1342- SK,    RIP1 and RIP3 contribute to shikonin-induced DNA double-strand breaks in glioma cells via increase of intracellular reactive oxygen species
- in-vitro, GBM, NA - in-vivo, NA, NA
"highlight2" >RIP1↑,
"highlight2" >RIP3↑,
"highlight2" >DNAdam↑, DNA DSBs in vitro and in vivo
"highlight2" >ROS↑,
"highlight2" >GSH↓, depletion of GSH

1312- SK,    Shikonin induces apoptosis through reactive oxygen species/extracellular signal-regulated kinase pathway in osteosarcoma cells
- in-vitro, OS, 143B
"highlight2" >ROS↑, Taken together, our results reveal that shikonin increased ROS generation and ERK activation, and reduced Bcl2, which consequently caused the cells to undergo apoptosis.
"highlight2" >p‑ERK↑, phosphorylated ERK was apparently increased in response to shikonin treatment for 24 and 48 h.
"highlight2" >Bcl-2↓,
"highlight2" >cl‑PARP↑, PARP cleavage, another well known characteristic of apoptosis, was also found in shikonin-treated cells.
"highlight2" >Apoptosis↑,
"highlight2" >TumCCA↑, 4 and 8mM shikonin for 24 h obviously caused G2/M phase arrest
"highlight2" >Bcl-2↑, shikonin also decreased Bcl-2 expression, and decreased the pro-caspase 3
"highlight2" >proCasp3↓,

1284- SK,    Shikonin induces ferroptosis in multiple myeloma via GOT1-mediated ferritinophagy
- in-vitro, Melanoma, RPMI-8226 - in-vitro, Melanoma, U266
"highlight2" >Ferroptosis↑, SHK treatment leads to the ferroptosis of MM cells
"highlight2" >LDH↓,
"highlight2" >ROS↑, Cellular mitochondrial lipid ROS also increased after SHK treatment
"highlight2" >Iron↑,
"highlight2" >lipid-P↑,
"highlight2" >ATP↓, extracellular release of Adenosine 5’-triphosphate (ATP) and High mobility group protein B1 (HMGB1
"highlight2" >HMGB1↓,
"highlight2" >GPx4↓, Additionally, the ferroptosis markers GPX4 and solute carrier family 7 member 11 (xCT/SLC7A11) were downregulated at both the transcriptional and translational levels after SHK treatment
"highlight2" >MDA↑, SHK treatment led to an increase in MDA content in cells. In contrast, the levels of SOD and GSH decreased in cells
"highlight2" >SOD↓,
"highlight2" >GSH↓,

1281- SK,    Enhancement of NK cells proliferation and function by Shikonin
- in-vivo, Colon, Caco-2
"highlight2" >Perforin↑,
"highlight2" >GranB↑,
"highlight2" >p‑ERK↑,
"highlight2" >p‑Akt↑,
"highlight2" >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
"highlight2" >eff↝, Meanwhile, Shikonin inhibits the cell proliferation at 100.0 ng/ml

1280- SK,    Shikonin Induces Apoptotic Cell Death via Regulation of p53 and Nrf2 in AGS Human Stomach Carcinoma Cells
- in-vitro, GC, AGS
"highlight2" >ROS↑, shikonin induced the generation of ROS as well as caspase 3-dependent apoptosis.
"highlight2" >Casp3↑,
"highlight2" >P53↑, shikonin induced p53 expression but repressed Nrf2 expression
"highlight2" >NRF2↓, Nrf2/ARE signaling pathway may be inhibited by shikonin treatment, especially at high concentration of 250 nM

1073- SK,  Chemo,    Natural Compound Shikonin Is a Novel PAK1 Inhibitor and Enhances Efficacy of Chemotherapy against Pancreatic Cancer Cells
- in-vitro, PC, PANC1 - in-vitro, PC, Bxpc-3
"highlight2" >PAK1↓, significantly inhibited the activity of PAK1 kinase
"highlight2" >TumCP↓,
"highlight2" >Apoptosis↑,
"highlight2" >ChemoSen↑, shikonin sensitized pancreatic cancer cells to chemotherapeutic
"highlight2" >ROS↑, Moreover, shikonin has been shown to trigger ROS-based mitochondria-mediated apoptosis and significantly inhibited tumor growth in a human colon cancer SW480 xenograft mouse model [18]

1050- SK,    Shikonin improves the effectiveness of PD-1 blockade in colorectal cancer by enhancing immunogenicity via Hsp70 upregulation
- in-vitro, Colon, CT26
"highlight2" >HSP70/HSPA5↑,
"highlight2" >ROS↑, upregulation of Hsp70 was dependent on ROS induced by SK
"highlight2" >PKM2↓,

1049- SK,    Shikonin inhibits immune checkpoint PD-L1 expression on macrophage in sepsis by modulating PKM2
- in-vivo, NA, NA
"highlight2" >TNF-α↓,
"highlight2" >IL6↓,
"highlight2" >IFN-γ↓,
"highlight2" >IL1β↓,
"highlight2" >PD-L1↓, Shikonin significantly decreased PD-L1 expression on macrophages, not PD-1 expression on T cells in vivo and in vitro.
"highlight2" >p‑PKM2↓,

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
"highlight2" >TumCG↓, SK inhibits tumor cell growth in estrogen receptor alpha (ERalpha)-positive, but not ERalpha-negative breast cancer cells.
"highlight2" >ERα↓, SK inhibits ERa expression, and suppresses ERa signaling
"highlight2" >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
"highlight2" >*toxicity↓, In addition, SK shows low cytoxicity in normal human mammary epithelia cells.

2199- SK,    Induction of Ferroptosis by Shikonin in Gastric Cancer via the DLEU1/mTOR/GPX4 Axis
- in-vitro, GC, NA
"highlight2" >ROS↑, Shikonin could induce reactive oxygen species (ROS), lipid ROS, intracellular ferrous iron (Fe2+), and malondialdehyde (MDA) in GC.
"highlight2" >lipid-P↑,
"highlight2" >Iron↑,
"highlight2" >MDA↑,
"highlight2" >GPx4↓, shikonin decreased the expression of GPX4 by suppressing GPX4 synthesis and decreasing ferritin.
"highlight2" >Ferritin↓,
"highlight2" >DLEU1↓, shikonin decreased DLEU1 expression in GC cells
"highlight2" >mTOR↓, shikonin might decrease GPX4 levels by inhibiting the DLEU1/mTOR pathway.
"highlight2" >Ferroptosis↑, shikonin-induced ferroptosis

2216- SK,    Shikonin upregulates the expression of drug-metabolizing enzymes and drug transporters in primary rat hepatocytes
- in-vivo, Nor, NA
"highlight2" >*NRF2↑, Shikonin effectively upregulates the transcription of CYP isozymes, phase II detoxification enzymes, and phase III membrane transporters and this function is at least partially through activation of AhR and Nrf2
"highlight2" >*AhR↑,
"highlight2" >*CYP1A1↑, shikonin dose-dependently increased the protein expression of CYP1A1, CYP1A2, CYP2C6, CYP2D1, and CYP3A2.
"highlight2" >*CYP1A2↑,
"highlight2" >*CYP2C6↑,
"highlight2" >*CYP2D1↑,
"highlight2" >*CYP3A2↑,
"highlight2" >*NQO1↑, Compared with the controls, cells treated with 2 uM shikonin had 5.5-, 3.0-, and 2.0-fold higher UGT1A1, NQO1, and PGST protein levels

2215- SK,  doxoR,    Shikonin alleviates doxorubicin-induced cardiotoxicity via Mst1/Nrf2 pathway in mice
- in-vivo, Nor, NA
"highlight2" >*cardioP↑, Mice receiving shikonin showed reduced cardiac injury response and enhanced cardiac function after DOX administration
"highlight2" >*ROS↓, Shikonin significantly attenuated DOX-induced oxidative damage, inflammation accumulation and cardiomyocyte apoptosis.
"highlight2" >*Inflam↓,
"highlight2" >*Mst1↓, Shikonin protects against DOX-induced cardiac injury by inhibiting Mammalian sterile 20-like kinase 1 (Mst1) and oxidative stress and activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.
"highlight2" >*NRF2↑,
"highlight2" >*eff↓, Nrf2 knockdown counteracted the protective effects of shikonin on cardiac injury and dysfunction caused by DOX in mice
"highlight2" >*antiOx↑, Previous studies have shown that shikonin possesses direct and indirect antioxidant properties, as evidenced by its ability to restore SOD expression and GSH levels, as well as block oxidative stress
"highlight2" >*SOD↑,
"highlight2" >*GSH↑,
"highlight2" >*TNF-α↓, shikonin decreased the elevlated cardiac TNF-α induced by DOX
"highlight2" >BAX↓, Shikonin attenuated DOX-induced upregulation of Bax and the down-regulation of Bcl-2
"highlight2" >Bcl-2↑,

2214- SK,    Shikonin Attenuates Cochlear Spiral Ganglion Neuron Degeneration by Activating Nrf2-ARE Signaling Pathway
- in-vitro, Nor, NA
"highlight2" >*NRF2↑, shikonin can increase the expression of Nrf2 and its downstream molecules HO-1 and NQO1, thereby enhancing the antioxidant capacity of SGNs and SGSs
"highlight2" >*HO-1↑,
"highlight2" >*NQO1↑,
"highlight2" >*antiOx↑,
"highlight2" >*neuroP↑, shikonin pretreatment has a defensive effect on auditory nerve damage.
"highlight2" >*ROS↓, shikonin pretreatment can also significantly reduce the high levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in SGNs caused by ouabain, and increase the levels of superoxide dismutase (SOD) and reduced glutathione (GSH) expression
"highlight2" >*MDA↓,
"highlight2" >*SOD↑,
"highlight2" >GSH↑,

2213- SK,    Shikonin attenuates cerebral ischemia/reperfusion injury via inhibiting NOD2/RIP2/NF-κB-mediated microglia polarization and neuroinflammation
- in-vivo, Stroke, NA
"highlight2" >*neuroP↑, Shikonin treatment significantly reduced brain infarction volume and improved neurological function in MCAO/R rats.
"highlight2" >*Inflam↓, Shikonin treatment significantly reduced microglial proinflammatory phenotype and levels of proinflammatory markers (inducible-NO synthase (iNOS), tumor necrosis factor-alpha (TNF-α),
"highlight2" >*iNOS↓,
"highlight2" >*TNF-α↓,
"highlight2" >*IL1β↓, interleukin-1 beta (IL-1β), and IL-6), increased microglial anti-inflammatory phenotype and levels of anti-inflammatory markers (Arginase-1 (Arg1), transforming growth factor-beta (TGF-β), and IL-10),
"highlight2" >*IL6↓,
"highlight2" >*ARG↑,
"highlight2" >*TGF-β↑,
"highlight2" >*IL10↑,
"highlight2" >*NF-kB↓, reversed the expression of Nucleotide-binding oligomerization domain 2 (NOD2) and phosphorylation receptor interacting protein 2 (p-RIP2), and suppressed nuclear factor kappa-B (NF-κB) signaling activation in the ischemic penumbra regions.
"highlight2" >*eff↓, Furthermore, overexpression of NOD2 markedly attenuated the neuroprotective effects of Shikonin treatment in MCAO/R rats.

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
"highlight2" >FLT3↓, SHK suppresses the expression and phosphorylation of FLT3 receptors and their downstream molecules
"highlight2" >NF-kB↓, Inhibition of the NF-κB/miR-155 pathway is an important mechanism through which SHK kills FLT3-AML cells
"highlight2" >miR-155↓,
"highlight2" >Diff↑, Moreover, a low concentration of SHK promotes the differentiation of AML cells with FLT3-ITD mutations.
"highlight2" >TumCG↓, Finally, SHK could significantly inhibit the growth of MV4-11 cells in leukemia bearing mice.

2211- SK,    Shikonin mitigates ovariectomy-induced bone loss and RANKL-induced osteoclastogenesis via TRAF6-mediated signaling pathways
- in-vivo, ostP, NA
"highlight2" >*BMD↑, Shikonin prevented bone loss by inhibiting osteoclastogenesis in vitro and improving bone loss in ovariectomized mice in vivo.
"highlight2" >*p‑NF-kB↓, shikonin inhibited the phosphorylation of inhibitor of NF-κB (IκB), P50, P65, extracellular regulated protein kinases (ERK), c-Jun N-terminal kinase (JNK), and P38.
"highlight2" >*p‑p50↓, by inhibiting phosphorylation of P65, P50, and IkB protein.
"highlight2" >*p‑p65↓,
"highlight2" >*p‑ERK↓, shikonin blocked the MAPK pathway via preventing phosphorylation of ERK, JNK, and P38
"highlight2" >*p‑cJun↓,
"highlight2" >*p‑p38↓,

2210- SK,    Shikonin inhibits the cell viability, adhesion, invasion and migration of the human gastric cancer cell line MGC-803 via the Toll-like receptor 2/nuclear factor-kappa B pathway
- in-vitro, BC, MGC803
"highlight2" >TumCA↓, Shikonin (1 μm) inhibited significantly the adhesion, invasion and migratory ability of MGC-803 cells.
"highlight2" >TumCI↓,
"highlight2" >TumCMig↓,
"highlight2" >MMP2↓, matrix metalloproteinases (MMP)-2, MMP-7, TLR2 and p65 NF-κB
"highlight2" >MMP7↓,
"highlight2" >TLR2↓,
"highlight2" >p65↓,
"highlight2" >NF-kB↓,
"highlight2" >eff↑, In addition, the co-incubation of Shikonin and anti-TLR2/MG-132 has a significant stronger activity than anti-TLR2 or MG-132 alone.
"highlight2" >ROS↑, Shikonin-induced ROS generation

2209- SK,    Shikonin inhibits tumor invasion via down-regulation of NF-κB-mediated MMP-9 expression in human ACC-M cells
- in-vitro, adrenal, ACC-M
"highlight2" >MMP9↓, MMP-9 were significantly suppressed by increasing Shikonin concentrations.
"highlight2" >NF-kB↓, down-regulation of MMP-9 appeared to be via the inactivation of NF-κB as the treatment with Shikonin suppressed the protein level of phosphate-IkBa
"highlight2" >IKKα↓,

2203- SK,    Shikonin suppresses small cell lung cancer growth via inducing ATF3-mediated ferroptosis to promote ROS accumulation
- in-vitro, Lung, NA
"highlight2" >TumCP↓, shikonin effectively suppressed cell proliferation, apoptosis, migration, invasion, and colony formation and slightly induced apoptosis in SCLC cells
"highlight2" >Apoptosis↓,
"highlight2" >TumCMig↓,
"highlight2" >TumCI↓,
"highlight2" >Ferroptosis↑, shikonin could also induced ferroptosis in SCLC cells
"highlight2" >ERK↓, Shikonin treatment effectively suppressed the activation of ERK, the expression of ferroptosis inhibitor GPX4, and elevated the level of 4-HNE, a biomarker of ferroptosis
"highlight2" >GPx4↓,
"highlight2" >4-HNE↑, elevated the level of 4-HNE, a biomarker of ferroptosis
"highlight2" >ROS↑, ROS and lipid ROS were increased, while the GSH levels were decreased in SCLC cells after shikonin treatment.
"highlight2" >GSH↓,
"highlight2" >ATF3↑, shikonin activated ATF3 transcription by impairing the recruitment of HDAC1 mediated by c-myc on the ATF3 promoter, and subsequently elevating of histone acetylation
"highlight2" >HDAC1↓,
"highlight2" >ac‑Histones↑,

2202- SK,    Enhancing Tumor Therapy of Fe(III)-Shikonin Supramolecular Nanomedicine via Triple Ferroptosis Amplification
- in-vitro, Var, NA
"highlight2" >Iron↑, After delivering into glutathione (GSH)-overexpressed tumor cells, FeShik will disassemble and release Fe2+ to induce cell death via ferroptosis.
"highlight2" >Ferroptosis↑,
"highlight2" >pH↝, GOx executes its catalytic activity to produce an acid environment and plenty of H2O2 for stimulating •OH generation via the Fenton reaction
"highlight2" >H2O2↑,
"highlight2" >ROS↑,
"highlight2" >Fenton↑,
"highlight2" >GSH↓, SRF will suppress the biosynthesis of GSH by inhibiting system Xc-, further deactivating the enzymatic activity of glutathione peroxidase 4 (GPX4).
"highlight2" >GPx4↓,
"highlight2" >lipid-P↑, Up-regulation of the oxidative stress level and down-regulation of GPX4 expression can dramatically accelerate the accumulation of lethal lipid peroxides, leading to ferroptosis amplification of tumor cells

2201- SK,    Shikonin promotes ferroptosis in HaCaT cells through Nrf2 and alleviates imiquimod-induced psoriasis in mice
- in-vitro, PSA, HaCaT - in-vivo, NA, NA
"highlight2" >*eff↑, SHK treatment significantly improved imiquimod (IMQ)-induced psoriasis symptoms in mice
"highlight2" >*IL6↓, attenuated the production of inflammatory cytokines, including interleukin (IL)-6, IL-17, and tumor necrosis factor-alpha (i.e., TNF-α)
"highlight2" >*IL17↓,
"highlight2" >*TNF-α↓,
"highlight2" >*lipid-P↑, enhancing intracellular and mitochondrial ferrous and lipid peroxidation levels
"highlight2" >*NRF2↓, by regulating expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear receptor coactivator 4 (NCOA4) and glutathione peroxidase 4 (GPX4)
"highlight2" >*HO-1↝,
"highlight2" >*NCOA4↝,
"highlight2" >*GPx4↓, low dose SHK on LPS inhibited GPX4 and Nrf2 expression
"highlight2" >*Ferroptosis↓, inhibited ferroptosis in psoriatic skin by reducing inflammation, ameliorating oxidative stress and iron accumulation.
"highlight2" >*Inflam↓,
"highlight2" >*ROS↓,
"highlight2" >*Iron↓,

2200- SK,    Shikonin inhibits the growth of anaplastic thyroid carcinoma cells by promoting ferroptosis and inhibiting glycolysis
- in-vitro, Thyroid, CAL-62 - in-vitro, Thyroid, 8505C
"highlight2" >NF-kB↓, SKN inhibits the expression of NF-κB,GPX4,TXNRD1,PKM2,GLUT1.
"highlight2" >GPx4↓,
"highlight2" >TrxR1↓, TXNRD1
"highlight2" >PKM2↓,
"highlight2" >GLUT1↓,
"highlight2" >Glycolysis↓, inhibiting glycolysis in ATC cells.
"highlight2" >Ferroptosis↑, SKN in inducing intracellular ferroptosis
"highlight2" >GlucoseCon↓, Measurements of glucose uptake after 1, 3, and 5 μM concentrations of SKN treatment for 24 h showed a decrease in both cells
"highlight2" >lactateProd↓, Lactate production in the cells decreased with the rise of SKN treatment concentration
"highlight2" >ROS↑, cellular ROS increased significantly with the rise in SKN concentration

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
"highlight2" >Hif1a↓, shikonin inhibited HIF-1α protein synthesis without affecting the expression of HIF-1α mRNA or degrading HIF-1α protein
"highlight2" >ROS↓, shikonin resulted in a significant decrease of hypoxia-induced ROS production in HCT116 and SW620 cells
"highlight2" >mTOR↓,
"highlight2" >p70S6↓,
"highlight2" >4E-BP1↓,
"highlight2" >eIF2α↓,
"highlight2" >TumCCA↑, HCT116 cells
"highlight2" >TumCP↓, HCT116 and SW620
"highlight2" >Half-Life↝, shikonin-treated cells (Fig. S1), showing the half-life was around 50 min in HCT116 and SW620 cells.

2198- SK,    Shikonin suppresses proliferation of osteosarcoma cells by inducing ferroptosis through promoting Nrf2 ubiquitination and inhibiting the xCT/GPX4 regulatory axis
- in-vitro, OS, MG63 - in-vitro, OS, 143B
"highlight2" >TumCP↓, shikonin significantly suppressed OS cells proliferation and blocked the cell cycle progression in vitro.
"highlight2" >TumCCA↑,
"highlight2" >Ferroptosis↑, ferroptosis in OS cells by promoting the Fe2+ accumulation, reactive oxygen species and lipid peroxidation formation, malondialdehyde production and mitochondrial damage
"highlight2" >Iron↑,
"highlight2" >ROS↑,
"highlight2" >lipid-P↑,
"highlight2" >MDA↑,
"highlight2" >mtDam↑,
"highlight2" >NRF2↓, influenced Nrf2 stability via inducing ubiquitin degradation, which suppressed the expression of Nrf2 downstream targets xCT and GPX4, and led to stimulating ferroptosis. Promoted Nrf2 degradation
"highlight2" >xCT↓,
"highlight2" >GPx4↓,
"highlight2" >GSH/GSSG↓, GSH/GSSG ratio declined after shikonin (1.5 uM) treatment
"highlight2" >Keap1↑, shikonin (1.5 uM) significantly downregulated the expression of Nrf2 and upregulated the expression of Keap1

2197- SK,    Shikonin derivatives for cancer prevention and therapy
- Review, Var, NA
"highlight2" >ROS↑, This compound accumulates in the mitochondria, which leads to the generation of reactive oxygen species (ROS), and deregulates intracellular Ca2+ levels.
"highlight2" >Ca+2↑,
"highlight2" >BAX↑, shikonin alone by increasing the expression of the pro-apoptotic Bax protein and decreasing the expression of the anti-apoptotic Bcl2 protein
"highlight2" >Bcl-2↓,
"highlight2" >MMP9↓, This treatment also inhibited metastasis by decreasing the expression of MMP-9 and NF-kB p65 without affecting MMP-2 expression.
"highlight2" >NF-kB↓,
"highlight2" >PKM2↓, Figure 4
"highlight2" >Hif1a↓,
"highlight2" >NRF2↓,
"highlight2" >P53↑,
"highlight2" >DNMT1↓,
"highlight2" >MDR1↓,
"highlight2" >COX2↓,
"highlight2" >VEGF↓,
"highlight2" >EMT↓,
"highlight2" >MMP7↓,
"highlight2" >MMP13↓,
"highlight2" >uPA↓,
"highlight2" >RIP1↑,
"highlight2" >RIP3↑,
"highlight2" >Casp3↑,
"highlight2" >Casp7↑,
"highlight2" >Casp9↑,
"highlight2" >P21↓,
"highlight2" >DFF45↓,
"highlight2" >TRAIL↑,
"highlight2" >PTEN↑,
"highlight2" >mTOR↓,
"highlight2" >AR↓,
"highlight2" >FAK↓,
"highlight2" >Src↓,
"highlight2" >Myc↓,
"highlight2" >RadioS↑, shikonin acted as a radiosensitizer because of the high ROS production it induced.

2196- SK,    Research progress in mechanism of anticancer action of shikonin targeting reactive oxygen species
- Review, Var, NA
"highlight2" >*ALAT↓, shikonin was found to mitigate the rise in ALT and AST levels triggered by LPS/GalN
"highlight2" >*AST↓,
"highlight2" >*Inflam?, demonstrated the anti-inflammatory properties of shikonin within two traditional mouse models frequently employed in pharmacological research to assess anti-inflammatory activities
"highlight2" >*EMT↑, Shikonin stimulates EMT by weakening the nuclear translocation of NF-κB p65
"highlight2" >ROS?, naphthoquinone framework possesses the capacity to produce ROS, which in turn modulate cellular oxidative stress levels
"highlight2" >TrxR1↓, Duan and colleagues demonstrated that shikonin specifically inhibits the physiological function of TrxR1 by targeting its Sec residue
"highlight2" >PERK↑, In vivo Western blot of HCT-15(colon cancer) xenografts showed shikonin upregulated PERK/eIF2α/ATF4/CHOP and IRE1α/JNK pathways.
"highlight2" >eIF2α↑,
"highlight2" >ATF4↑,
"highlight2" >CHOP↑,
"highlight2" >IRE1↑,
"highlight2" >JNK↑,
"highlight2" >eff↝, oral shikonin did not demonstrate anti-tumor effects in the colorectal cancer model, intraperitoneal injection significantly inhibited tumor growth.
"highlight2" >DR5↑, upregulation of Death Receptor 5 (DR5) in cholangiocarcinoma cells through ROS-induced activation of the JNK signaling cascade.
"highlight2" >Glycolysis↓, inhibited glycolysis in HepG2 cells by suppressing the activity of PKM2, a critical enzyme within the glycolytic pathway
"highlight2" >PKM2↓,
"highlight2" >ChemoSen↑, The combination of shikonin with drugs can reverse drug resistance and enhance therapeutic efficacy
"highlight2" >GPx4↓, shikonin conjunction with cisplatin overcame drug resistance in cancer cells, downregulated GPX4, and upregulated haemoglobin oxygenase 1 (HMOX1) inducing iron death in cells.
"highlight2" >HO-1↑,

2195- SK,    Shikonin induces ferroptosis in osteosarcomas through the mitochondrial ROS-regulated HIF-1α/HO-1 axis
- in-vitro, OS, NA
"highlight2" >TumCP↓, At a low dose, Shikonin inhibits OS progression and has a excellent biosafety.
"highlight2" >Ferroptosis↓, Shikonin induces ferroptosis in OS cel
"highlight2" >Hif1a↑, Shikonin upregualtes HIF-1α/HO-1 axis to produce excess Fe2+ which leads to ROS accumulation on OS cell, followed by ferroptosis.
"highlight2" >HO-1↑,
"highlight2" >Iron↑,
"highlight2" >ROS↑,
"highlight2" >GSH/GSSG↓, while simultaneously reducing the GSH/GSSG ratio and GPX4 and SLC7A11 expression
"highlight2" >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
"highlight2" >tumCV↓, Shikonin reduced esophageal cancer cells viability and induced cell cycle arrest and apoptosis.
"highlight2" >TumCCA↑,
"highlight2" >Apoptosis↑,
"highlight2" >EGFR↓, Shikonin decreased EGFR, PI3K, p-AKT, HIF1α and PKM2 expression
"highlight2" >PI3K↓,
"highlight2" >Hif1a↓,
"highlight2" >PKM2↓,
"highlight2" >cycD1↓, shikonin reduced the expression of PKM2, HIF1α and cyclinD1 in tumor tissues
"highlight2" >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
"highlight2" >*NF-kB↓, shikonin decreased nuclear factor-kappaB (NF-κB) activation
"highlight2" >*Hif1a↓, reduced both mRNA and protein levels of hypoxia-inducible factor-1 (HIF-1)α.
"highlight2" >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.

2192- SK,    Shikonin Inhibits Tumor Growth of ESCC by suppressing PKM2 mediated Aerobic Glycolysis and STAT3 Phosphorylation
- in-vitro, ESCC, KYSE-510 - in-vitro, ESCC, Eca109 - in-vivo, NA, NA
"highlight2" >TumCP↓, Shikonin effectively inhibited cell proliferation in dose-dependent and time-dependent manner compared with the control group
"highlight2" >Glycolysis↓, detection of glycolysis showed that Shikonin suppressed the glucose consumption, lactate production, glycolytic intermediates and pyruvate kinase enzymatic activity.
"highlight2" >GlucoseCon↓,
"highlight2" >lactateProd↓,
"highlight2" >PKM2↓,
"highlight2" >p‑PKM2↓, decreased the expression of p-PKM2 and p-STAT3 in vivo
"highlight2" >p‑STAT3↓,
"highlight2" >GLUT1↓, Shikonin suppressed the expression of GLUT1 and HK2 proteins which are related to glycolysis.
"highlight2" >HK2↓,
"highlight2" >TumW↓, tumor weight in the Shikonin group decreased by approximately 40% compared with the vehicle control group,

2191- SK,    Shikonin Suppresses Skin Carcinogenesis via Inhibiting Cell Proliferation
- in-vitro, Melanoma, NA
"highlight2" >PKM2↓, shikonin alone suppressed PKM2 activity
"highlight2" >ATF4↓, Shikonin decreased the nuclear levels of ATF2 and knockdown of ATF2 suppressed the expression levels of Cdk4 and Fra-1
"highlight2" >CDK4↓,
"highlight2" >COX2↓, shikonin has been shown to inhibit TPA-induced cyclooxygenase-2 (COX-2) activation, which is mediated by suppression of MAPK signaling
"highlight2" >MAPK↓,

2190- SK,    Shikonin exerts antitumor activity by causing mitochondrial dysfunction in hepatocellular carcinoma through PKM2-AMPK-PGC1α signaling pathway
- in-vitro, HCC, HCCLM3
"highlight2" >TumCP↓, shikonin inhibited the proliferation, migration, and invasiveness of HCCLM3 cells, and promoted cell apoptosis in a dose-dependent manner
"highlight2" >TumCMig↓,
"highlight2" >TumCI↓,
"highlight2" >Apoptosis↑,
"highlight2" >MMP↓, shikonin affected mitochondrial function by disrupting mitochondrial membrane potential and oxidative stress (OS) status.
"highlight2" >ROS↑,
"highlight2" >OCR↓, shikonin decreased the oxygen consumption rate of HCCLM3 cells, as well as the levels of ATP and metabolites involved in the tricarboxylic acid cycle (TCA cycle)
"highlight2" >ATP↓,
"highlight2" >PKM2↓, Shikonin decreased the expression of PKM2 in the mitochondria

2189- SK,    PKM2 inhibitor shikonin suppresses TPA-induced mitochondrial malfunction and proliferation of skin epidermal JB6 cells
- in-vitro, Melanoma, NA
"highlight2" >PKM2↓, shikonin suppressed the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) induced neoplastic cell transformation and PKM2 activation in the early stage of carcinogenesis.
"highlight2" >chemoP↑, results suggest that shikonin bears chemopreventive potential for human skin cancers in which PKM2 is upregulated,
"highlight2" >eff↝, PKM2 activity was increased by 2.5-fold in tumor samples than normal tissues
"highlight2" >lactateProd↓, Shikonin Suppressed TPA-Induced Lactate Production
"highlight2" >ROS↑, shikonin induces apoptosis in hepatocellular carcinoma cells by the reactive oxygen species (ROS)/Akt and RIP1/NF-κB pathways
"highlight2" >*ROS?, in our study, shikonin could preserve mitochondrial function and decrease the levels of ROS, leading to blocking PKM2 activation.
"highlight2" >*PKM2↓,

2188- SK,    Molecular mechanism of shikonin inhibiting tumor growth and potential application in cancer treatment
- Review, Var, NA
"highlight2" >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
"highlight2" >EGFR↓,
"highlight2" >PI3K↓,
"highlight2" >Akt↓,
"highlight2" >angioG↓,
"highlight2" >Apoptosis↑,
"highlight2" >Necroptosis↑,
"highlight2" >GSH↓, leading to the increased consumption of reduced glutathione (GSH) and increased Ca2+ concentration in the cells and destroying the mitochondrial membrane potential.
"highlight2" >Ca+2↓,
"highlight2" >MMP↓,
"highlight2" >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.
"highlight2" >p38↑,
"highlight2" >proCasp3↑,
"highlight2" >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
"highlight2" >VEGF↓, shikonin can inhibit the expression of VEGF
"highlight2" >FOXO3↑, Activated FOXO3a/EGR1/SIRT1 signaling
"highlight2" >EGR1↑,
"highlight2" >SIRT1↑,
"highlight2" >RIP1↑, Upregulation of RIP1 and RIP3
"highlight2" >RIP3↑,
"highlight2" >BioAv↓, limitations caused by its poor water solubility, it has a short half-life and nonselective biological distribution
"highlight2" >NF-kB↓, Shikonin can also prevent the activation of NF-κB by AKT and then downregulate the expression of Bcl-xl,
"highlight2" >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: 100

Results for Effect on Cancer/Diseased Cells:
4-HNE↑,1,   4E-BP1↓,1,   ADAM17↓,1,   AIF↑,1,   Akt↓,8,   p‑Akt↓,1,   p‑Akt↑,1,   AMPK↑,1,   angioG↓,1,   AntiCan↑,2,   AntiTum↑,2,   Apoptosis?,1,   Apoptosis↓,1,   Apoptosis↑,21,   AR↓,1,   ATF2↓,1,   ATF3↑,1,   ATF4↓,1,   ATF4↑,2,   ATP↓,6,   BAX↓,1,   BAX↑,4,   Bcl-2↓,8,   Bcl-2↑,2,   Bcl-xL↓,1,   Beclin-1↑,1,   BioAv↓,2,   Ca+2↓,1,   Ca+2↑,3,   mt-Ca+2↑,1,   cardioP↑,1,   Casp↑,4,   Casp3↑,8,   cl‑Casp3↓,1,   cl‑Casp3↑,2,   proCasp3↓,1,   proCasp3↑,1,   Casp7↑,1,   cl‑Casp8↑,1,   Casp9↑,5,   Catalase↓,2,   CD11b↑,1,   CD14↑,1,   CDK2↓,1,   CDK4↓,2,   chemoP↑,2,   ChemoSen↑,7,   CHOP↑,4,   cMyc↓,1,   COX2↓,3,   cycD1↓,5,   cycE↓,2,   Cyt‑c↑,4,   DFF45↓,1,   Diff↑,2,   DLEU1↓,1,   DNAdam↑,4,   DNMT1↓,2,   Dose↝,2,   DR5↑,1,   E-cadherin↑,2,   ECAR↓,1,   eff↓,13,   eff↑,6,   eff⇅,1,   eff↝,3,   EGFR↓,5,   EGR1↑,1,   eIF2α↓,1,   eIF2α↑,3,   p‑eIF2α↑,2,   EMT↓,3,   Endon↑,1,   ER Stress↑,3,   ERK↓,4,   ERK↑,1,   p‑ERK↓,2,   p‑ERK↑,2,   ERα↓,1,   FAK↓,2,   FASN↓,1,   Fenton↑,1,   Ferritin↓,1,   Ferroptosis↓,1,   Ferroptosis↑,6,   FLT3↓,1,   FOXO3↑,1,   G6PD↓,1,   GlucoseCon↓,11,   GLUT1↓,6,   GLUT1∅,1,   GLUT3↓,1,   GLUT3∅,1,   Glycolysis↓,19,   GPx↑,1,   GPx4↓,8,   GranB↑,1,   GRP58↓,1,   GRP78/BiP↑,1,   GSDME↑,1,   GSH↓,11,   GSH↑,1,   GSH/GSSG↓,4,   GSK‐3β↑,1,   GTPBP4↓,1,   GutMicro↑,1,   H2O2↑,2,   Half-Life↓,1,   Half-Life↝,2,   HDAC1↓,1,   Hif1a↓,6,   Hif1a↑,1,   ac‑Histones↑,1,   HK1↓,1,   HK2↓,5,   HMGB1↓,1,   HO-1↑,2,   HO-1⇅,1,   HSP70/HSPA5↑,1,   IFN-γ↓,1,   IGF-1↓,1,   p‑IGF-1↓,1,   IKKα↓,1,   IL1β↓,2,   IL6↓,3,   IRE1↑,1,   Iron↑,5,   ITGB1↓,1,   JAK1?,1,   p‑JAK1↓,1,   p‑JAK2↓,1,   JNK↑,3,   p‑JNK↑,1,   KDR/FLK-1↓,1,   Keap1↑,2,   lactateProd↓,17,   LC3B↑,1,   LC3B-II↑,1,   LC3I↑,1,   LDH↓,1,   LDH↝,1,   LDH∅,1,   LDHA∅,1,   lipid-P↑,5,   MAPK↓,1,   Mcl-1↓,1,   MDA↑,3,   MDR1↓,1,   miR-155↓,1,   MMP↓,14,   MMP13↓,2,   MMP2↓,2,   MMP3↓,1,   MMP7↓,2,   MMP9↓,4,   MMPs↓,1,   mtDam↑,1,   mTOR↓,6,   mTOR↑,1,   Myc↓,1,   N-cadherin↓,1,   Necroptosis↑,7,   NF-kB↓,9,   NK cell↑,1,   Nrf1↑,1,   NRF2↓,4,   OCR↓,1,   OS↑,3,   other↓,1,   other↑,1,   other↝,1,   OXPHOS⇅,1,   P21↓,1,   P21↑,2,   p38↓,1,   p38↑,2,   p‑p38↑,1,   P53↑,7,   p62↑,1,   p65↓,1,   p70S6↓,1,   PAK1↓,1,   PARP↑,1,   cl‑PARP↑,7,   PD-L1↓,1,   PDH∅,1,   PDK1↓,2,   Perforin↑,1,   PERK↑,3,   PFK1↓,1,   PFK2↓,1,   PFKFB2↓,1,   pH↝,1,   PI3K↓,8,   PKM2↓,36,   PKM2∅,1,   p‑PKM2↓,2,   PTEN↑,2,   PYCR1↓,1,   Pyro↑,1,   QoL↑,1,   RadioS↑,1,   Remission↑,1,   RIP1↓,2,   RIP1↑,5,   RIP3↓,1,   RIP3↑,5,   ROS?,1,   ROS↓,1,   ROS↑,40,   i-ROS↑,1,   selectivity↑,11,   SIRT1↑,1,   SIRT2↑,1,   Snail↓,1,   SOD↓,1,   SOD1↑,1,   Src↓,2,   Src↑,1,   p‑STAT3↓,2,   survivin↓,1,   TAMS↝,1,   TGF-β↓,2,   TIMP1↑,1,   TLR2↓,1,   TNF-α↓,2,   TRAIL↑,1,   TrxR↓,1,   TrxR1↓,3,   TumAuto↑,4,   TumCA↓,1,   TumCCA↓,1,   TumCCA↑,11,   TumCD↑,1,   TumCG↓,10,   TumCI↓,12,   TumCMig↓,13,   TumCP↓,19,   tumCV↓,7,   TumMeta↓,1,   TumVol↓,4,   TumW↓,3,   uPA↓,1,   VCAM-1↓,1,   VEGF↓,2,   Vim↓,1,   VM↓,1,   Warburg↓,3,   Weight↑,1,   xCT↓,1,   XIAP↓,1,   YAP/TEAD↓,1,   β-catenin/ZEB1↓,1,  
Total Targets: 253

Results for Effect on Normal Cells:
AhR↑,1,   AIM2↓,1,   Akt↑,1,   p‑Akt↑,1,   ALAT↓,3,   AMPK↑,1,   antiOx↑,4,   Apoptosis↓,2,   ARG↑,1,   AST↓,3,   BAX↓,3,   Bcl-2↑,3,   BDNF↑,1,   BioAv↓,2,   BioAv↑,2,   BMD↑,1,   cardioP↑,1,   Casp1↓,1,   Casp12↓,1,   Casp3↓,1,   Casp3↑,1,   cl‑Casp3↓,1,   Catalase↑,1,   CHOP↓,1,   p‑cJun↓,1,   cognitive↑,2,   COX2↓,1,   CYP1A1↑,1,   CYP1A2↑,1,   CYP2C6↑,1,   CYP2D1↑,1,   CYP3A2↑,1,   Dose↝,1,   E-sel↓,1,   eff↓,3,   eff↑,2,   p‑eIF2α↓,1,   EMT↑,1,   ER Stress↓,1,   ERK↓,1,   p‑ERK↓,1,   Ferroptosis↓,1,   GCLC↑,1,   GPx↑,1,   GPx4↓,1,   GRP78/BiP↓,1,   GSH↑,5,   GSS↑,1,   Half-Life↝,1,   hepatoP↑,3,   Hif1a↓,1,   HMGB1↓,1,   HO-1↑,5,   HO-1↝,1,   ICAM-1↓,1,   IFN-γ↓,1,   p‑IKKα↓,1,   IL10↓,1,   IL10↑,1,   IL17↓,2,   IL18↓,1,   IL1β↓,4,   IL6↓,5,   IL8↓,1,   Inflam?,1,   Inflam↓,7,   iNOS↓,2,   Iron↓,1,   JNK↓,1,   lactateProd↓,1,   lipid-P↑,1,   MDA↓,2,   MMP↓,1,   motorD↑,1,   MPO↓,3,   Mst1↓,1,   NCOA4↝,1,   neuroP↑,5,   NF-kB↓,3,   NF-kB↑,1,   p‑NF-kB↓,1,   NHE3↑,1,   NLRP3↓,1,   NO↓,1,   NQO1↑,2,   NRF2↓,1,   NRF2↑,10,   other↑,1,   p38↓,1,   p‑p38↓,1,   p‑p50↓,1,   p‑p65↓,1,   PI3K↑,1,   PKM2↓,3,   p‑PTEN↓,1,   RenoP↑,3,   ROS?,1,   ROS↓,9,   ROS↑,1,   Sepsis↓,1,   SIRT1↓,1,   SIRT1↑,1,   SOD↑,6,   STAT3↑,1,   TAC↑,1,   TGF-β↑,1,   TNF-α↓,7,   toxicity↓,3,   toxicity∅,2,   TumCG↓,1,   VCAM-1↓,1,  
Total Targets: 111

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:150  Target#:%  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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