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

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

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

-Note half-life15-30mins or 8hr?.
BioAv low, poor water solubility
Pathways:
- usually induce ROS production in cancer cells, and reduce ROS in normal cells.
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓,
- Lowers AntiOxidant defense in Cancer Cells: NRF2↓, TrxR↓**, SOD↓, GSH↓ Catalase↓ GPx4↓
- Raises AntiOxidant defense in Normal Cells: ROS↓">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


ROS, Reactive Oxygen Species: Click to Expand ⟱
Source: HalifaxProj (inhibit)
Type:
Reactive oxygen species (ROS) are highly reactive molecules that contain oxygen and can lead to oxidative stress in cells. They play a dual role in cancer biology, acting as both promoters and suppressors of cancer.
ROS can cause oxidative damage to DNA, leading to mutations that may contribute to cancer initiation and progression. So normally you want to inhibit ROS to prevent cell mutations.
However excessive ROS can induce apoptosis (programmed cell death) in cancer cells, potentially limiting tumor growth. Chemotherapy typically raises ROS.

"Reactive oxygen species (ROS) are two electron reduction products of oxygen, including superoxide anion, hydrogen peroxide, hydroxyl radical, lipid peroxides, protein peroxides and peroxides formed in nucleic acids 1. They are maintained in a dynamic balance by a series of reduction-oxidation (redox) reactions in biological systems and act as signaling molecules to drive cellular regulatory pathways."
"During different stages of cancer formation, abnormal ROS levels play paradoxical roles in cell growth and death 8. A physiological concentration of ROS that maintained in equilibrium is necessary for normal cell survival. Ectopic ROS accumulation promotes cell proliferation and consequently induces malignant transformation of normal cells by initiating pathological conversion of physiological signaling networks. Excessive ROS levels lead to cell death by damaging cellular components, including proteins, lipid bilayers, and chromosomes. Therefore, both scavenging abnormally elevated ROS to prevent early neoplasia and facilitating ROS production to specifically kill cancer cells are promising anticancer therapeutic strategies, in spite of their contradictoriness and complexity."
"ROS are the collection of derivatives of molecular oxygen that occur in biology, which can be categorized into two types, free radicals and non-radical species. The non-radical species are hydrogen peroxide (H 2O 2 ), organic hydroperoxides (ROOH), singlet molecular oxygen ( 1 O 2 ), electronically excited carbonyl, ozone (O3 ), hypochlorous acid (HOCl, and hypobromous acid HOBr). Free radical species are super-oxide anion radical (O 2•−), hydroxyl radical (•OH), peroxyl radical (ROO•) and alkoxyl radical (RO•) [130]. Any imbalance of ROS can lead to adverse effects. H2 O 2 and O 2 •− are the main redox signalling agents. The cellular concentration of H2 O 2 is about 10−8 M, which is almost a thousand times more than that of O2 •−".
"Radicals are molecules with an odd number of electrons in the outer shell [393,394]. A pair of radicals can be formed by breaking a chemical bond or electron transfer between two molecules."

Recent investigations have documented that polyphenols with good antioxidant activity may exhibit pro-oxidant activity in the presence of copper ions, which can induce apoptosis in various cancer cell lines but not in normal cells. "We have shown that such cell growth inhibition by polyphenols in cancer cells is reversed by copper-specific sequestering agent neocuproine to a significant extent whereas iron and zinc chelators are relatively ineffective, thus confirming the role of endogenous copper in the cytotoxic action of polyphenols against cancer cells. Therefore, this mechanism of mobilization of endogenous copper." > Ions could be one of the important mechanisms for the cytotoxic action of plant polyphenols against cancer cells and is possibly a common mechanism for all plant polyphenols. In fact, similar results obtained with four different polyphenolic compounds in this study, namely apigenin, luteolin, EGCG, and resveratrol, strengthen this idea.
Interestingly, the normal breast epithelial MCF10A cells have earlier been shown to possess no detectable copper as opposed to breast cancer cells [24], which may explain their resistance to polyphenols apigenin- and luteolin-induced growth inhibition as observed here (Fig. 1). We have earlier proposed [25] that this preferential cytotoxicity of plant polyphenols toward cancer cells is explained by the observation made several years earlier, which showed that copper levels in cancer cells are significantly elevated in various malignancies. Thus, because of higher intracellular copper levels in cancer cells, it may be predicted that the cytotoxic concentrations of polyphenols required would be lower in these cells as compared to normal cells."

Majority of ROS are produced as a by-product of oxidative phosphorylation, high levels of ROS are detected in almost all cancers.
-It is well established that during ER stress, cytosolic calcium released from the ER is taken up by the mitochondrion to stimulate ROS overgeneration and the release of cytochrome c, both of which lead to apoptosis.

Note: Products that may raise ROS can be found using this database, by:
Filtering on the target of ROS, and selecting the Effect Direction of ↑

Targets to raise ROS (to kill cancer cells):
• NADPH oxidases (NOX): NOX enzymes are involved in the production of ROS.
    -Targeting NOX enzymes can increase ROS levels and induce cancer cell death.
    -eNOX2 inhibition leads to a high NADH/NAD⁺ ratio which can lead to increased ROS
• Mitochondrial complex I: Inhibiting can increase ROS production
• P53: Activating p53 can increase ROS levels(by inducing the expression of pro-oxidant genes)
• Nrf2: regulates the expression of antioxidant genes. Inhibiting Nrf2 can increase ROS levels
• Glutathione (GSH): an antioxidant. Depleting GSH can increase ROS levels
• Catalase: Catalase converts H2O2 into H2O+O. Inhibiting catalase can increase ROS levels
• SOD1: converts superoxide into hydrogen peroxide. Inhibiting SOD1 can increase ROS levels
• PI3K/AKT pathway: regulates cell survival and metabolism. Inhibiting can increase ROS levels
• HIF-1α: regulates genes involved in metabolism and angiogenesis. Inhibiting HIF-1α can increase ROS
• Glycolysis: Inhibiting glycolysis can increase ROS levels • Fatty acid oxidation: Cancer cells often rely on fatty acid oxidation for energy production.
-Inhibiting fatty acid oxidation can increase ROS levels
• ER stress: Endoplasmic reticulum (ER) stress can increase ROS levels
• Autophagy: process by which cells recycle damaged organelles and proteins.
-Inhibiting autophagy can increase ROS levels and induce cancer cell death.
• KEAP1/Nrf2 pathway: regulates the expression of antioxidant genes.
    -Inhibiting KEAP1 or activating Nrf2 can increase ROS levels and induce cancer cell death.
• DJ-1: regulates the expression of antioxidant genes. Inhibiting DJ-1 can increase ROS levels
• PARK2: regulates the expression of antioxidant genes. Inhibiting PARK2 can increase ROS levels
• SIRT1:regulates the expression of antioxidant genes. Inhibiting SIRT1 can increase ROS levels
• AMPK: regulates energy metabolism and can increase ROS levels when activated.
• mTOR: regulates cell growth and metabolism. Inhibiting mTOR can increase ROS levels
• HSP90: regulates protein folding and can increase ROS levels when inhibited.
• Proteasome: degrades damaged proteins. Inhibiting the proteasome can increase ROS levels
• Lipid peroxidation: a process by which lipids are oxidized, leading to the production of ROS.
    -Increasing lipid peroxidation can increase ROS levels
• Ferroptosis: form of cell death that is regulated by iron and lipid peroxidation.
    -Increasing ferroptosis can increase ROS levels
• Mitochondrial permeability transition pore (mPTP): regulates mitochondrial permeability.
    -Opening the mPTP can increase ROS levels
• BCL-2 family proteins: regulate apoptosis and can increase ROS levels when inhibited.
• Caspase-independent cell death: a form of cell death that is regulated by ROS.
    -Increasing caspase-independent cell death can increase ROS levels
• DNA damage response: regulates the repair of DNA damage. Increasing DNA damage can increase ROS
• Epigenetic regulation: process by which gene expression is regulated.
    -Increasing epigenetic regulation can increase ROS levels

-PKM2, but not PKM1, can be inhibited by direct oxidation of cysteine 358 as an adaptive response to increased intracellular reactive oxygen species (ROS)

ProOxidant Strategy:(inhibit the Melavonate Pathway (likely will also inhibit GPx)
-HydroxyCitrate (HCA) found as supplement online and typically used in a dose of about 1.5g/day or more
-Atorvastatin typically 40-80mg/day
-Dipyridamole typically 200mg 2x/day
-Lycopene typically 100mg/day range

Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy

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
Apoptosis↑, Shikonin induces apoptosis and autophagy in A375 cells and inhibits their proliferation
TumAuto↑,
TumCP↓,
TumCCA↑, Shikonin caused G2/M phase arrest through upregulation of p21 and downregulation of cyclin B1
P21↑,
cycD1↓,
ER Stress↑, Shikonin significantly triggered ER stress-mediated apoptosis by upregulating the expression of p-eIF2α, CHOP, and cleaved caspase-3.
p‑eIF2α↑,
CHOP↑,
cl‑Casp3↑,
p38↑, induced protective autophagy by activating the p38 pathway, followed by an increase in the levels of p-p38, LC3B-II, and Beclin 1
LC3B-II↑,
Beclin-1↑,
ROS↑, Shikonin increased the production of reactive oxygen species
eff↓, NAC treatment significantly decreased the expression of p-p38, LC3B-II, and Beclin 1.

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

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

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

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
selectivity↑, In vitro, SHK suppresses proliferation and triggers cell death of gastric cancer cells but leads minor damage to gastric epithelial cells.
TumCP↓,
TumCD↑,
ROS↑, SHK induces the generation of intracellular reactive oxygen species (ROS), depolarizes the mitochondrial membrane potential (MMP) and ultimately triggers mitochondria-mediated apoptosis.
MMP↓,
Casp↑, SHK induces apoptosis of gastric cancer cells not only in a caspase-dependent manner which releases Cytochrome C and triggers the caspase cascade
Cyt‑c↑,
Endon↑, nuclear translocation of AIF and Endonuclease G
AIF↑,
eff↓, NAC and GSH significantly inhibited SHK-induced death
ChemoSen↑, SHK enhances chemotherapeutic sensitivity of 5-fluorouracil and oxaliplatin
TumCCA↑, SHK caused S-phase cell cycle arrest in SGC-7901 and BGC-823 gastric cancer cells
GSH/GSSG↓, We found that the GSH/GSSG ratio was significantly decreased when treated with SHK.
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
selectivity↑, shikonin induced apoptosis of Huh7 and BEL7402 but not nontumorigenic cells.
ROS↑, ROS generation was detected
eff↓, ROS scavengers completely inhibited shikonin-induced apoptosis, indicating that ROS play an essential role
Akt↓, downregulation of Akt and RIP1/NF-κB activity was found to be involved in shikonin-induced apoptosis
RIP1↓,
NF-kB↓,

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

2221- SK,    Shikonin Induces Apoptosis, Necrosis, and Premature Senescence of Human A549 Lung Cancer Cells through Upregulation of p53 Expression
- in-vitro, Lung, A549
Apoptosis↑, shikonin significantly induced cell apoptosis and reduced proliferation in a dose-dependent manner.
TumCP↓,
tumCV↓, shikonin (1–2.5 μg/mL) cause viability reduction
Necroptosis↑, while higher concentrations (5–10 μg/mL) precipitate both apoptosis and necrosis.
P53↑, via p53-mediated cell fate pathways
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
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
*RenoP↑, Shikonin significantly and dose-dependently alleviated gentamicin-induced renal injury, as revealed by restoring normal kidney function and histological architecture.
*ROS↓, Shikonin Defended against Renal Oxidative Stress and Activated the SIRT1/Nrf2/HO-1 Cascades in Rats with Gentamicin-Induced Renal Damage
*SIRT1↓,
*NRF2↑,
*HO-1↑,
*GSH↑, significant rise in GSH, TAC levels, and SOD activity, as well as SIRT1, Nrf2, and HO-1 protein levels
*TAC↑,
*SOD↑,
*MDA↓, significant decrease in the renal MDA, NO, and iNOS
*NO↓,
*iNOS↓,
*NHE3↑, shikonin treatment significantly and dose-dependently enhanced the reduced NHE3 level and mRNA expression induced by repeated gentamicin injections,
*PI3K↑, in the current study, shikonin treatment of the gentamicin-injected groups increased PI3K

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

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

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

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
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).
Glycolysis↓, Collectively, these data suggest that shikonin exerts its cytotoxicity by inhibiting glycolysis and inducing ATP depletion, most likely due to inhibition of PKM2.
ATP↓, Only the highest concentration of shikonin (5 µM) induced a significant ATP depletion between 15 min and 6 h
PKM2↓,
TumCMig↓, Shikonin reduces PDAC cell migration
Ca+2↑, Shikonin induces cytotoxic Ca2+ overload
GlucoseCon↓, shikonin inhibited glucose consumption and lactate production with an IC50 of 5–10 μM in MCF-7 cells that exclusively express PKM2
lactateProd↓,
MMP↓, Shikonin is also reported to impair mitochondrial function and increase oxidative stress
ROS↑,

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
*TNF-α↓, Our results showed that SHK treatment distinctly decreased serum TNF-a, IL-1b, IL-6 and IFN-g inflammatory cytokine production
*IL1β↓,
*IL6↓,
*IFN-γ↓,
*ALAT↓, , reduced serum ALT, AST, hepatic MPO and ROS production levels,
*AST↓,
*MPO↓,
*ROS↓,
*JNK↓, inhibited JNK1/2, ERK1/2, p38 and NF-kB (p65) phosphorylation, and suppressed IkBa phosphorylation and degradation.
*ERK↓,
*p38↓,
*NF-kB↓,
*p‑IKKα↓,
*SOD↑, SHK could dramatically increase SOD and GSH production, as well as reduce ROS production,
*GSH↑,
*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.
*NRF2↑,
*hepatoP↑,

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

3040- SK,    Pharmacological Properties of Shikonin – A Review of Literature since 2002
- Review, Var, NA - Review, IBD, NA - Review, Stroke, NA
*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.
*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
*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.
*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
*Inflam↓, anti-inflammatory effect of shikonin
*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.
*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.
*MPO↓, MPO activity was reduced as well as the expression of COX-2, the activation of NF-κB and that of STAT3.
*COX2↓,
*NF-kB↑,
*STAT3↑,
*antiOx↑, Antioxidant Effects of Shikonin
*ROS↓, radical scavenging activity of shikonin
*neuroP↑, shown to exhibit a neuroprotective effect against the damage caused by ischemia/reperfusion in adult male Kunming mice
*SOD↑, it also attenuated neuronal damage and the upregulation of superoxide dismutase, catalase, and glutathione peroxidase activities while reducing the glutathione/glutathione disulfide ratio.
*Catalase↑,
*GPx↑,
*Bcl-2↑, shikonin upregulated Bcl-2, downregulated Bax and prevented cell nuclei from undergoing morphological changes typical of apoptosis.
*BAX↓,
cardioP↑, Two different studies have suggested a possible cardioprotective effect of shikonin that would be related to its anti-inflammatory and antioxidant effects.
AntiCan↑, A wide spectrum of anticancer mechanisms of action have been described for shikonin:
NF-kB↓, suppression of NF-κB-regulated gene products [44],
ROS↑, ROS generation [46],
PKM2↓, inhibition of tumor-specific pyruvate kinase-M2 [47,48]
TumCCA↑, cell cycle arrest [49]
Necroptosis↑, or induction of necroptosis [50],
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
DNAdam↑,
MMP↓,
Cyt‑c↑, At 10 μM, shikonin induced a greater release of cytochrome c from the mitochondria and of lactate dehydrogenase,
LDH↝,

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

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
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
ROS↑,
lactateProd↓,
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
cl‑Casp3↓,
PKM2↓,
GLUT1↓,
HK2↓,
LC3B↑,

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

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
RIP1↑, we found shikonin activated RIP1 and RIP3 in glioma cells in vitro and in vivo, which was accompanied with glycolysis suppression
RIP3↑,
Glycolysis↓,
G6PD↓, shikonin-induced decreases of glucose-6-phosphate and pyruvate and downregulation of HK II and PKM2
HK2↓,
PKM2↓,
H2O2↑, shikonin also triggered accumulation of intracellular H2O2 and depletion of GSH and cysteine
GSH↓,
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
CD14↑,
CD11b↑,
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.
GSH↓,
GSH/GSSG↓,
GPx↑, mRNA expression levels of GPX and CAT were markedly upregulated by Shikonin in a dose-dependent manner
Catalase↓, Shikonin causes apoptosis in human glioma cells by interrupting intracellular redox homeostasis, which included CAT downregulation
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
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.
PKM2↓,
Apoptosis↑,
ROS↑,
OXPHOS⇅, Shikonin up-regulated mitochondrial biogenesis to increase mitochondrial oxidative phosphorylation in HepG2 cells, but displayed the opposite trend in HCCLM3 cells.
eff↓, insensitivity of HCCLM3 cells to shikonin treatment.

2011- SK,    Shikonin Attenuates Acetaminophen-Induced Hepatotoxicity by Upregulation of Nrf2 through Akt/GSK3β Signaling
- in-vitro, Nor, HL7702 - in-vivo, Nor, NA
*NRF2↑, Shikonin (SHK) enhances Nrf2 in multiple lines of normal cells.
*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
*ALAT↓, reversed the levels of serum alanine/aspartate aminotransferases (ALT/AST)
*AST↓,
*MPO↓,
*ROS↓, neutralized oxidative stress in APAP-treated human normal liver L-02 cells
*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
EGFR↓, Shikonin is a potent inhibitor of EGFR
selectivity↑, Shikonin exhibited selective cytotoxicity among two NSCLC cell lines (H1975 and H1650) and one normal lung fibroblast cell line (CCD-19LU).
Casp↑, Shikonin significantly increased the activity of caspases and poly (ADP-ribosyl) polymerase (PARP), which are indicators of apoptosis
PARP↑,
Apoptosis↑,
ROS↑, intensity of ROS by greater than 10-fold
eff↓, NAC, an inhibitor of ROS, completely blocked apoptosis, caspase and PARP activation induced by Shikonin.
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
TumCG↓, shikonin has a selective inhibitory effect on bladder cancer cells
selectivity↑, and has no toxicity on normal bladder epithelial cells
*toxicity∅,
Necroptosis↑, shikonin induced necroptosis and impaired autophagic flux via ROS generation
ROS↑,
p62↑, accumulation of autophagic biomarker p62 elevated p62/Keap1 complex and activated the Nrf2 signaling pathway to fight against ROS
Keap1↑,
*NRF2↑, activated the Nrf2 signaling pathway to fight against ROS
eff↑, we further combined shikonin with late autophagy inhibitor(chloroquine) to treat bladder cancer and achieved a better inhibitory effect.

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
ChemoSen↑, combination of shikonin and cisplatin exhibited synergistic anticancer efficacy
selectivity↑, and achieved greater selectivity between cancer cells and normal cells.
i-ROS↑, By inducing intracellular oxidative stress, shikonin potentiated cisplatin-induced DNA damage, followed by increased activation of mitochondrial pathway.
DNAdam↑,
MMP↓,
TumCCA↑, induction of G2/M cell cycle arrest
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
*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
tumCV↓, We found that shikonin has strong cytotoxic effects on 15 cancer cell lines, including multidrug-resistant cell lines.
selectivity↑, structure of mitochondria show marked differences between cancer cells and normal cells
Dose↝, Shikonin inhibited proliferation by 50% in nearly all cancer cell lines at concentrations below 10 μM after 24 h.
other↑, mitochondrion itself is a possible target of the compound
MMP↓, Breakdown of the Mitochondrial Membrane Potential
ROS↑, ROS production shortly after cellular shikonin uptake, and ROS levels continuously increased for at least 1 h after exposure to shikonin
DNAdam↑, Induction of ROS, oxidative DNA damage, and elevated intracellular Ca2+ levels by shikonin
Ca+2↑,
Casp9↑, Caspase 9 is activated after the release of cytochrome c from the mitochondria
Cyt‑c↑,
*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
NRF2↓, ROS production by shikonin resulted in the inhibition of nuclear translocation of Nrf2
ROS↑, ROS generation from mitochondrial complex II
Apoptosis↑,
Cyt‑c↑, release cytochrome c to the cytosol
GSH↓,
MMP↓,
P53↑,
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.

1344- SK,    Novel multiple apoptotic mechanism of shikonin in human glioma cells
- in-vitro, GBM, U87MG - in-vitro, GBM, Hs683 - in-vitro, GBM, M059K
ROS↑,
GSH↓,
MMP↓,
P53↑, upregulation of p53,
cl‑PARP↑,
Catalase↓,
SOD1↑,
Bcl-2↓,
BAX↑,
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
*BioAv↓, clinical use is limited by poor tumor targeting and low bioavailability
ROS↑,
GSH↓,
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
RIP1↑,
RIP3↑,
DNAdam↑, DNA DSBs in vitro and in vivo
ROS↑,
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
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.
p‑ERK↑, phosphorylated ERK was apparently increased in response to shikonin treatment for 24 and 48 h.
Bcl-2↓,
cl‑PARP↑, PARP cleavage, another well known characteristic of apoptosis, was also found in shikonin-treated cells.
Apoptosis↑,
TumCCA↑, 4 and 8mM shikonin for 24 h obviously caused G2/M phase arrest
Bcl-2↑, shikonin also decreased Bcl-2 expression, and decreased the pro-caspase 3
proCasp3↓,

1284- SK,    Shikonin induces ferroptosis in multiple myeloma via GOT1-mediated ferritinophagy
- in-vitro, Melanoma, RPMI-8226 - in-vitro, Melanoma, U266
Ferroptosis↑, SHK treatment leads to the ferroptosis of MM cells
LDH↓,
ROS↑, Cellular mitochondrial lipid ROS also increased after SHK treatment
Iron↑,
lipid-P↑,
ATP↓, extracellular release of Adenosine 5’-triphosphate (ATP) and High mobility group protein B1 (HMGB1
HMGB1↓,
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
MDA↑, SHK treatment led to an increase in MDA content in cells. In contrast, the levels of SOD and GSH decreased in cells
SOD↓,
GSH↓,

1280- SK,    Shikonin Induces Apoptotic Cell Death via Regulation of p53 and Nrf2 in AGS Human Stomach Carcinoma Cells
- in-vitro, GC, AGS
ROS↑, shikonin induced the generation of ROS as well as caspase 3-dependent apoptosis.
Casp3↑,
P53↑, shikonin induced p53 expression but repressed Nrf2 expression
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
PAK1↓, significantly inhibited the activity of PAK1 kinase
TumCP↓,
Apoptosis↑,
ChemoSen↑, shikonin sensitized pancreatic cancer cells to chemotherapeutic
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
HSP70/HSPA5↑,
ROS↑, upregulation of Hsp70 was dependent on ROS induced by SK
PKM2↓,

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

2215- SK,  doxoR,    Shikonin alleviates doxorubicin-induced cardiotoxicity via Mst1/Nrf2 pathway in mice
- in-vivo, Nor, NA
*cardioP↑, Mice receiving shikonin showed reduced cardiac injury response and enhanced cardiac function after DOX administration
*ROS↓, Shikonin significantly attenuated DOX-induced oxidative damage, inflammation accumulation and cardiomyocyte apoptosis.
*Inflam↓,
*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.
*NRF2↑,
*eff↓, Nrf2 knockdown counteracted the protective effects of shikonin on cardiac injury and dysfunction caused by DOX in mice
*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
*SOD↑,
*GSH↑,
*TNF-α↓, shikonin decreased the elevlated cardiac TNF-α induced by DOX
BAX↓, Shikonin attenuated DOX-induced upregulation of Bax and the down-regulation of Bcl-2
Bcl-2↑,

2214- SK,    Shikonin Attenuates Cochlear Spiral Ganglion Neuron Degeneration by Activating Nrf2-ARE Signaling Pathway
- in-vitro, Nor, NA
*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
*HO-1↑,
*NQO1↑,
*antiOx↑,
*neuroP↑, shikonin pretreatment has a defensive effect on auditory nerve damage.
*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
*MDA↓,
*SOD↑,
GSH↑,

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
TumCA↓, Shikonin (1 μm) inhibited significantly the adhesion, invasion and migratory ability of MGC-803 cells.
TumCI↓,
TumCMig↓,
MMP2↓, matrix metalloproteinases (MMP)-2, MMP-7, TLR2 and p65 NF-κB
MMP7↓,
TLR2↓,
p65↓,
NF-kB↓,
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.
ROS↑, Shikonin-induced ROS generation

2203- SK,    Shikonin suppresses small cell lung cancer growth via inducing ATF3-mediated ferroptosis to promote ROS accumulation
- in-vitro, Lung, NA
TumCP↓, shikonin effectively suppressed cell proliferation, apoptosis, migration, invasion, and colony formation and slightly induced apoptosis in SCLC cells
Apoptosis↓,
TumCMig↓,
TumCI↓,
Ferroptosis↑, shikonin could also induced ferroptosis in SCLC cells
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
GPx4↓,
4-HNE↑, elevated the level of 4-HNE, a biomarker of ferroptosis
ROS↑, ROS and lipid ROS were increased, while the GSH levels were decreased in SCLC cells after shikonin treatment.
GSH↓,
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
HDAC1↓,
ac‑Histones↑,

2202- SK,    Enhancing Tumor Therapy of Fe(III)-Shikonin Supramolecular Nanomedicine via Triple Ferroptosis Amplification
- in-vitro, Var, NA
Iron↑, After delivering into glutathione (GSH)-overexpressed tumor cells, FeShik will disassemble and release Fe2+ to induce cell death via ferroptosis.
Ferroptosis↑,
pH↝, GOx executes its catalytic activity to produce an acid environment and plenty of H2O2 for stimulating •OH generation via the Fenton reaction
H2O2↑,
ROS↑,
Fenton↑,
GSH↓, SRF will suppress the biosynthesis of GSH by inhibiting system Xc-, further deactivating the enzymatic activity of glutathione peroxidase 4 (GPX4).
GPx4↓,
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
*eff↑, SHK treatment significantly improved imiquimod (IMQ)-induced psoriasis symptoms in mice
*IL6↓, attenuated the production of inflammatory cytokines, including interleukin (IL)-6, IL-17, and tumor necrosis factor-alpha (i.e., TNF-α)
*IL17↓,
*TNF-α↓,
*lipid-P↑, enhancing intracellular and mitochondrial ferrous and lipid peroxidation levels
*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)
*HO-1↝,
*NCOA4↝,
*GPx4↓, low dose SHK on LPS inhibited GPX4 and Nrf2 expression
*Ferroptosis↓, inhibited ferroptosis in psoriatic skin by reducing inflammation, ameliorating oxidative stress and iron accumulation.
*Inflam↓,
*ROS↓,
*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
NF-kB↓, SKN inhibits the expression of NF-κB,GPX4,TXNRD1,PKM2,GLUT1.
GPx4↓,
TrxR1↓, TXNRD1
PKM2↓,
GLUT1↓,
Glycolysis↓, inhibiting glycolysis in ATC cells.
Ferroptosis↑, SKN in inducing intracellular ferroptosis
GlucoseCon↓, Measurements of glucose uptake after 1, 3, and 5 μM concentrations of SKN treatment for 24 h showed a decrease in both cells
lactateProd↓, Lactate production in the cells decreased with the rise of SKN treatment concentration
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
Hif1a↓, shikonin inhibited HIF-1α protein synthesis without affecting the expression of HIF-1α mRNA or degrading HIF-1α protein
ROS↓, shikonin resulted in a significant decrease of hypoxia-induced ROS production in HCT116 and SW620 cells
mTOR↓,
p70S6↓,
4E-BP1↓,
eIF2α↓,
TumCCA↑, HCT116 cells
TumCP↓, HCT116 and SW620
Half-Life↝, shikonin-treated cells (Fig. S1), showing the half-life was around 50 min in HCT116 and SW620 cells.

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
TumCP↓, shikonin significantly suppressed OS cells proliferation and blocked the cell cycle progression in vitro.
TumCCA↑,
Ferroptosis↑, ferroptosis in OS cells by promoting the Fe2+ accumulation, reactive oxygen species and lipid peroxidation formation, malondialdehyde production and mitochondrial damage
Iron↑,
ROS↑,
lipid-P↑,
MDA↑,
mtDam↑,
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
xCT↓,
GPx4↓,
GSH/GSSG↓, GSH/GSSG ratio declined after shikonin (1.5 uM) treatment
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
ROS↑, This compound accumulates in the mitochondria, which leads to the generation of reactive oxygen species (ROS), and deregulates intracellular Ca2+ levels.
Ca+2↑,
BAX↑, shikonin alone by increasing the expression of the pro-apoptotic Bax protein and decreasing the expression of the anti-apoptotic Bcl2 protein
Bcl-2↓,
MMP9↓, This treatment also inhibited metastasis by decreasing the expression of MMP-9 and NF-kB p65 without affecting MMP-2 expression.
NF-kB↓,
PKM2↓, Figure 4
Hif1a↓,
NRF2↓,
P53↑,
DNMT1↓,
MDR1↓,
COX2↓,
VEGF↓,
EMT↓,
MMP7↓,
MMP13↓,
uPA↓,
RIP1↑,
RIP3↑,
Casp3↑,
Casp7↑,
Casp9↑,
P21↓,
DFF45↓,
TRAIL↑,
PTEN↑,
mTOR↓,
AR↓,
FAK↓,
Src↓,
Myc↓,
RadioS↑, shikonin acted as a radiosensitizer because of the high ROS production it induced.

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

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

2190- SK,    Shikonin exerts antitumor activity by causing mitochondrial dysfunction in hepatocellular carcinoma through PKM2-AMPK-PGC1α signaling pathway
- in-vitro, HCC, HCCLM3
TumCP↓, shikonin inhibited the proliferation, migration, and invasiveness of HCCLM3 cells, and promoted cell apoptosis in a dose-dependent manner
TumCMig↓,
TumCI↓,
Apoptosis↑,
MMP↓, shikonin affected mitochondrial function by disrupting mitochondrial membrane potential and oxidative stress (OS) status.
ROS↑,
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)
ATP↓,
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
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.
chemoP↑, results suggest that shikonin bears chemopreventive potential for human skin cancers in which PKM2 is upregulated,
eff↝, PKM2 activity was increased by 2.5-fold in tumor samples than normal tissues
lactateProd↓, Shikonin Suppressed TPA-Induced Lactate Production
ROS↑, shikonin induces apoptosis in hepatocellular carcinoma cells by the reactive oxygen species (ROS)/Akt and RIP1/NF-κB pathways
*ROS?, in our study, shikonin could preserve mitochondrial function and decrease the levels of ROS, leading to blocking PKM2 activation.
*PKM2↓,

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


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 52

Results for Effect on Cancer/Diseased Cells:
4-HNE↑,1,   4E-BP1↓,1,   ADAM17↓,1,   AIF↑,1,   Akt↓,5,   angioG↓,1,   AntiCan↑,2,   Apoptosis?,1,   Apoptosis↓,1,   Apoptosis↑,14,   AR↓,1,   ATF2↓,1,   ATF3↑,1,   ATF4↑,2,   ATP↓,4,   BAX↓,1,   BAX↑,2,   Bcl-2↓,6,   Bcl-2↑,2,   Bcl-xL↓,1,   Beclin-1↑,1,   BioAv↓,2,   Ca+2↓,1,   Ca+2↑,3,   cardioP↑,1,   Casp↑,4,   Casp3↑,5,   cl‑Casp3↓,1,   cl‑Casp3↑,1,   proCasp3↓,1,   proCasp3↑,1,   Casp7↑,1,   Casp9↑,3,   Catalase↓,2,   CD11b↑,1,   CD14↑,1,   chemoP↑,1,   ChemoSen↑,4,   CHOP↑,3,   COX2↓,2,   cycD1↓,3,   cycE↓,1,   Cyt‑c↑,4,   DFF45↓,1,   Diff↑,1,   DLEU1↓,1,   DNAdam↑,4,   DNMT1↓,1,   Dose↝,1,   DR5↑,1,   ECAR↓,1,   eff↓,13,   eff↑,3,   eff↝,2,   EGFR↓,2,   EGR1↑,1,   eIF2α↓,1,   eIF2α↑,2,   p‑eIF2α↑,2,   EMT↓,1,   Endon↑,1,   ER Stress↑,2,   ERK↓,4,   p‑ERK↓,1,   p‑ERK↑,1,   FAK↓,2,   Fenton↑,1,   Ferritin↓,1,   Ferroptosis↓,1,   Ferroptosis↑,6,   FOXO3↑,1,   G6PD↓,1,   GlucoseCon↓,2,   GLUT1↓,3,   Glycolysis↓,7,   GPx↑,1,   GPx4↓,8,   GRP58↓,1,   GRP78/BiP↑,1,   GSDME↑,1,   GSH↓,11,   GSH↑,1,   GSH/GSSG↓,4,   H2O2↑,2,   Half-Life↓,1,   Half-Life↝,2,   HDAC1↓,1,   Hif1a↓,3,   Hif1a↑,1,   ac‑Histones↑,1,   HK2↓,3,   HMGB1↓,1,   HO-1↑,2,   HO-1⇅,1,   HSP70/HSPA5↑,1,   IL6↓,1,   IRE1↑,1,   Iron↑,5,   JAK1?,1,   p‑JAK1↓,1,   p‑JAK2↓,1,   JNK↑,2,   p‑JNK↑,1,   Keap1↑,2,   lactateProd↓,4,   LC3B↑,1,   LC3B-II↑,1,   LDH↓,1,   LDH↝,1,   lipid-P↑,5,   MDA↑,3,   MDR1↓,1,   MMP↓,12,   MMP13↓,2,   MMP2↓,2,   MMP7↓,2,   MMP9↓,2,   MMPs↓,1,   mtDam↑,1,   mTOR↓,5,   Myc↓,1,   Necroptosis↑,5,   NF-kB↓,7,   NRF2↓,4,   OCR↓,1,   other↑,1,   OXPHOS⇅,1,   P21↓,1,   P21↑,2,   p38↑,2,   p‑p38↑,1,   P53↑,5,   p62↑,1,   p65↓,1,   p70S6↓,1,   PAK1↓,1,   PARP↑,1,   cl‑PARP↑,6,   PDK1↓,1,   PERK↑,2,   pH↝,1,   PI3K↓,3,   PKM2↓,14,   PTEN↑,1,   Pyro↑,1,   RadioS↑,1,   RIP1↓,2,   RIP1↑,4,   RIP3↓,1,   RIP3↑,4,   ROS?,1,   ROS↓,1,   ROS↑,40,   i-ROS↑,1,   selectivity↑,8,   SIRT1↑,1,   SIRT2↑,1,   SOD↓,1,   SOD1↑,1,   Src↓,2,   p‑STAT3↓,1,   TAMS↝,1,   TLR2↓,1,   TRAIL↑,1,   TrxR↓,1,   TrxR1↓,3,   TumAuto↑,3,   TumCA↓,1,   TumCCA↑,9,   TumCD↑,1,   TumCG↓,5,   TumCI↓,4,   TumCMig↓,5,   TumCP↓,11,   tumCV↓,2,   TumMeta↓,1,   uPA↓,1,   VEGF↓,2,   xCT↓,1,  
Total Targets: 179

Results for Effect on Normal Cells:
Akt↑,1,   ALAT↓,3,   AMPK↑,1,   antiOx↑,4,   Apoptosis↓,2,   AST↓,3,   BAX↓,1,   Bcl-2↑,2,   BioAv↓,2,   BioAv↑,2,   cardioP↑,1,   Casp3↓,1,   Casp3↑,1,   Catalase↑,1,   COX2↓,1,   Dose↝,1,   E-sel↓,1,   eff↓,1,   eff↑,1,   EMT↑,1,   ERK↓,1,   Ferroptosis↓,1,   GCLC↑,1,   GPx↑,1,   GPx4↓,1,   GSH↑,5,   GSS↑,1,   Half-Life↝,1,   hepatoP↑,3,   HO-1↑,4,   HO-1↝,1,   ICAM-1↓,1,   IFN-γ↓,1,   p‑IKKα↓,1,   IL10↓,1,   IL17↓,2,   IL1β↓,2,   IL6↓,4,   IL8↓,1,   Inflam?,1,   Inflam↓,5,   iNOS↓,1,   Iron↓,1,   JNK↓,1,   lipid-P↑,1,   MDA↓,2,   MMP↓,1,   MPO↓,3,   Mst1↓,1,   NCOA4↝,1,   neuroP↑,2,   NF-kB↓,1,   NF-kB↑,1,   NHE3↑,1,   NO↓,1,   NQO1↑,1,   NRF2↓,1,   NRF2↑,8,   other↑,1,   p38↓,1,   PI3K↑,1,   PKM2↓,1,   RenoP↑,2,   ROS?,1,   ROS↓,9,   ROS↑,1,   SIRT1↓,1,   SOD↑,6,   STAT3↑,1,   TAC↑,1,   TNF-α↓,6,   toxicity↓,2,   toxicity∅,1,   TumCG↓,1,   VCAM-1↓,1,  
Total Targets: 75

Scientific Paper Hit Count for: ROS, Reactive Oxygen Species
52 Shikonin
1 Cisplatin
1 Chemotherapy
1 doxorubicin
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:150  Target#:275  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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