Shikonin Cancer Research Results

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">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

Rank	Pathway / Target Axis	Direction	Primary Effect	Notes / Cancer Relevance
1	PKM2-mediated aerobic glycolysis (Warburg metabolism)	↓	Energy / biomass restriction	Key, repeatedly reported mechanism: shikonin suppresses PKM2 activity and PKM2-driven glycolysis in multiple tumor models, with downstream growth inhibition and apoptosis
2	ROS accumulation / oxidative stress	↑ ROS	Redox overload	Common upstream trigger that drives mitochondrial dysfunction and regulated cell death programs; often precedes necroptosis/apoptosis signaling
3	Necroptosis core cascade (RIPK1 → RIPK3 → MLKL)	↑	Programmed necrotic cell death	Strong evidence across cancers (e.g., leukemia and nasopharyngeal carcinoma): shikonin increases RIPK1/RIPK3/MLKL expression/activation; necroptosis inhibitors can blunt the effect
4	Mitochondrial integrity (ΔΨm)	↓	Mitochondrial dysfunction	ROS-linked depolarization; acts as a pivot into intrinsic apoptosis and other death programs
5	Intrinsic apoptosis (BAX/BAK → Caspase-9/3)	↑	Programmed cell death	Frequently observed; often framed as ROS → mitochondrial damage → caspase-dependent apoptosis
6	PKM2/STAT3 signaling axis	↓	Reduced survival & proliferation signaling	In ESCC and related models, shikonin suppresses PKM2-driven glycolysis and down-modulates STAT3 pathway activity
7	NF-κB pathway	↓	Reduced pro-survival transcription	Reported as part of multi-target suppression of inflammatory/anti-apoptotic programs in several tumor models and reviews
8	PI3K–AKT (± mTOR)	↓	Growth & resistance pathway inhibition	Often described as sensitizing cells to apoptosis/TRAIL; may be secondary to oxidative stress and metabolic collapse
9	Stress MAPKs (JNK / p38)	↑	Pro-death stress signaling	Common downstream response to ROS; can reinforce apoptosis and other death outcomes
10	Ferroptosis-related axis (lipid peroxidation; GPX4)	↑ lipid perox / ↓ GPX4	Iron-dependent oxidative death	Reported prominently for acetylshikonin (a shikonin derivative): ROS-associated lipid peroxidation with reduced GPX4 expression alongside RIPK1/RIPK3/MLKL activation
11	Endoplasmic reticulum stress (UPR / ERS)	↑	Proteotoxic stress signaling	Frequently mentioned in leukemia-focused mechanism summaries and broader reviews as contributory to growth arrest and death
12	Multiple regulated death programs (apoptosis / necroptosis / ferroptosis / pyroptosis)	↑ (context-dependent)	Broader cell-death engagement	Recent reviews emphasize that shikonin can engage several programmed cell death modalities depending on cell context and dosing

Rank	Pathway / Target Axis	Direction	Primary Effect	Notes / Cancer Relevance	Ref
1	PKM2-mediated aerobic glycolysis (Warburg metabolism)	↓ PKM2 activity / ↓ glycolysis	Energy & biomass restriction	Demonstrates shikonin (and analogs) inhibit cancer glycolysis, reducing glucose consumption/lactate production via PKM2 targeting	(ref)
2	PKM2 → STAT3 signaling axis	↓ PKM2-driven signaling / ↓ STAT3 pathway	Reduced survival & proliferation	ESCC study: shikonin suppresses PKM2-mediated aerobic glycolysis and regulates PKM2/STAT3 signaling	(ref)
3	Necroptosis (RIPK1 → RIPK3 → MLKL)	↑ RIPK1/RIPK3/MLKL	Programmed necrotic cell death	Nasopharyngeal carcinoma: shikonin induces necroptosis with upregulation of RIPK1/RIPK3/MLKL (with ROS involvement)	(ref)
4	ROS accumulation	↑ ROS	Oxidative stress trigger	Colon cancer model: shikonin increases intracellular ROS; ROS functions upstream of apoptosis	(ref)
5	Mitochondrial apoptosis (Caspase-9/3)	↑ Caspase-9/3	Programmed cell death	Same colon cancer study shows shikonin increases caspase-3 and caspase-9 activity (mitochondria-mediated apoptosis)	(ref)
6	ER stress / UPR (PERK → eIF2α → CHOP)	↑	Proteotoxic stress apoptosis signaling	Colon cancer: shikonin-induced apoptosis mediated by PERK/eIF2α/CHOP ER-stress pathway	(ref)
7	Autophagic flux (autophagosome–lysosome completion)	↓ autophagic flux (blocked)	ROS + apoptosis amplification	Colorectal cancer: shikonin induces ROS and apoptosis by inhibiting autophagic flux	(ref)
8	NF-κB signaling	↓ NF-κB activity	Reduced pro-survival transcription	Pancreatic cancer xenograft/mechanistic study: shikonin suppresses NF-κB activity and NF-κB–regulated gene products	(ref)
9	PI3K–AKT–mTOR (stemness / chemoresistance axis)	↓ PI3K/AKT/mTOR	Reduced survival & stemness	Chemoresistant lung cancer CSC context: shikonin attenuates PI3K–Akt–mTOR pathway and reduces cancer stemness	(ref)
10	Cell cycle control (p21; G2/M arrest)	↑ p21 / ↑ G2/M arrest	Proliferation block	Gastric cancer (AGS): shikonin induces cell-cycle arrest linked to p21 regulation	(ref)
11	Invasion / metastasis programs (NF-κB-linked)	↓ invasion	Anti-invasive phenotype	Reports shikonin inhibits tumor invasion via down-regulation of NF-κB–related mechanisms in a high-metastatic tumor model	(ref)
12	Chemosensitization via glycolysis suppression	↓ glycolysis / ↑ cisplatin sensitivity	Combination benefit	NSCLC: shikonin inhibits glycolysis and sensitizes cells to cisplatin (explicitly connecting metabolic suppression to chemosensitization)	(ref)

Scientific Papers found: Click to Expand⟱

2232-

SK,

Shikonin Induces Autophagy and Apoptosis in Esophageal Cancer EC9706 Cells by Regulating the AMPK/mTOR/ULK Axis

in-vitro,

ESCC,

EC9706

2.26 ± 0.12 µM

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.
TumCMig↓,
TumCI↓,
TumAuto↑,
Apoptosis↑,
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
BAX↑,
cl‑Casp3↑,
cl‑Casp8↑,
cl‑PARP↑,
AMPK↑, Shikonin-Induced Autophagy and Apoptosis Through Activation of AMPK/mTOR/ULK Pathway
mTOR↑,
TumVol↓, The tumor diameter is reduced by more than 25%, the response rate is 37%, and the 1-year survival rate is 47%
OS↑,
LC3I↑, Similarly, shikonin can upregulate the protein expression of LC3 in EC9706 cells

2364-

SK,

Pyruvate Kinase M2 Mediates Glycolysis Contributes to Psoriasis by Promoting Keratinocyte Proliferation

in-vivo,

PSA,

For 2-DG or Shikonin treatment, mice were intraperitoneally injected with 2-DG (500 mg/kg in saline, daily for 5 days) or Shikonin (25 mg/kg in saline/1% DMSO. daily for 5 days).

mice

eff↑, Shikonin or 2-DG treatment significantly attenuated the severity of skin lesions in animals
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
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,

mice

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.
lactateProd↓,
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,

Rat C6 tumor xenograft in nude mice

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

2361-

SK,

Natural shikonin and acetyl-shikonin improve intestinal microbial and protein composition to alleviate colitis-associated colorectal cancer

in-vivo,

CRC,

mice

GutMicro↑, Both SK and acetyl-SK decreased AOM/DSS-induced CAC, and regulated the intestinal flora structure in CAC mouse model
Dose↝, 20 mg/kg SK exhibited the most effective functions, even better than the positive drug mesalazine.
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)
IL6↓,
TNF-α↓,
PKM2↓,

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

4 or 8 umol/L

in-vitro,

NPC,

SUNE-1

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

2359-

SK,

Regulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted delivery

in-vivo,

Liver,

mice

TumCG↓, SHK@HA-MPDA achieved tumor-targeted delivery via hyaluronic acid-mediated binding with the tumor-associated CD44, and efficiently arrested colorectal tumor growth
PKM2↓, The inhibition of PKM2 by SHK@HA-MPDA led to the remodeling of the tumor immune microenvironment
EMT↓, reversing EMT by lactate abatement and the suppression of TGFβ signaling
TGF-β↓,
Glycolysis↓, EMT reversal by suppressing glycolysis and lactate production
lactateProd↓,
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,

mice

*eff↑, inhibition of PKM2 by shikonin or PKM2-IN-1 alleviates parkinsonism in mice
*PKM2↓,
*motorD↑, Behavioral tests showed that shikonin treatment improved the performance on rotarod, tail suspension, and olfaction (Figure 7B).
*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,

182 patients with HCC undergoing curative hepatectomy

in-vivo,

NA,

mouse

AntiTum↑, Shikonin exerted a remarkable antitumor effect in many tumors.
GTPBP4↓, We found that, first Shikonin could inhibit the binding of GTPBP4 and PKM2 proteins
PKM2↓,
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
GlucoseCon↓,
Glycolysis↓, Shikonin could suppress HCC growth and glycolysis through inhibiting PKM2 dependent glucose metabolism
E-cadherin↑, Downregulation of E-cadherin in GTPBP4 overexpression PLC/PRF/51 xenografts was also rescued by Shikonin treatment
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,

(1 mg/kg) by intraperitoneal injection once every 3 days

mice

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.
Glycolysis↓, Shikonin inhibited glycolysis in OV90 cells
FASN↓,
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
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.
TumCG↓, Shikonin itself significantly inhibited tumor growth
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,

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-ÎºB 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↓,

2354-

SK,

PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation

in-vivo,

Sepsis,

mice

PKM2↓, Shikonin is a potent PKM2 inhibitor in cancer cells and macrophages
*PKM2↓,
*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
*IL18↓,
*HMGB1↓,
*Casp1↓, shikonin significantly inhibited caspase-1 activation triggered by stimulation with ATP
*NLRP3↓, pharmacologic inhibition of PKM2 by shikonin selectively suppresses NLRP3 and AIM2 inflammasome activation.
*AIM2↓,
*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.
*Sepsis↓,

2234-

SK,

Shikonin Suppresses Cell Tumorigenesis in Gastric Cancer Associated with the Inhibition of c-Myc and Yap-1

in-vitro,

GC,

TumCP↓, proliferation rate, migration, and invasion ability of the gastric cancer cell group decreased significantly after shikonin intervention for 24h
TumCI↓,
TumCMig↓,
cMyc↓, expression levels of c-Myc and Yap-1 in gastric cancer cells were found to be significantly decreased after shikonin intervention
YAP/TEAD↓,

2233-

SK,

Clinical trial on the effects of shikonin mixture on later stage lung cancer

Trial,

Lung,

19 cases of later-stage lung cancer

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

2370-

SK,

The role of pyruvate kinase M2 in anticancer therapeutic treatments

Review,

Var,

Glycolysis↓, In summary, shikonin is able to inhibit tumor growth by suppressing aerobic glycolysis, which is mediated by PKM2 in vivo
PKM2↓,
EGFR↓, another study indicated that shikonin reduced epidermal growth factor receptor, PI3K, p-AKT, Hypoxia inducible factor-1α (HIF-1α) and PKM2 expression levels
PI3K↓,
p‑Akt↓,
Hif1a↓,

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

3 µM after 48 h

Apoptosis↑, Shikonin induced apoptotic cell death by activating mitogen-activated protein kinase family members
ER Stress↑, apoptotic process was mediated by the activation of endoplasmic reticulum (ER) stress
PERK↑, leading to activation of the PERK/elF2α/CHOP apoptotic pathway, and mitochondrial Ca2+ accumulation.
eIF2α↑,
CHOP↑,
mt-Ca+2↑,
MMP↓, Shikonin increased mitochondrial membrane depolarization
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.
Casp3↑,
Casp9↑,
ERK↑, Shikonin treatment activated ERK, JNK, and p38 MAPK in a time-dependent manner
JNK↑,
p38↓,

2230-

SK,

Shikonin induces ROS-based mitochondria-mediated apoptosis in colon cancer

in-vitro,

CRC,

HCT116

in-vivo,

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/CCND1↓, 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

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/CCND1↓,
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.

2228-

SK,

Shikonin induced Apoptosis Mediated by Endoplasmic Reticulum Stress in Colorectal Cancer Cells

in-vitro,

CRC,

HCT116

0.25, 0.5, 1, 1.5, 2, 2.5 and 3 μM

in-vitro,

CRC,

HCT15

in-vivo,

NA,

 intraperitoneal injection (3 mg/kg, 3 times per week

mouse

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

13.35uM

in-vitro,

GC,

SGC-7901

9.63uM

in-vitro,

Nor,

GES-1

>20 μM

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↑,

2224-

SK,

Shikonin induces apoptosis and autophagy via downregulation of pyrroline-5-carboxylate reductase1 in hepatocellular carcinoma cells

in-vitro,

HCC,

SMMC-7721 cell

in-vitro,

HCC,

HUH7

in-vitro,

HCC,

HepG2

PYCR1↓, SK may induce apoptosis and autophagy by reducing the expression of PYCR1 and suppressing PI3K/Akt/mTOR
PI3K↓,
Akt↓,
mTOR↓,
eff↑, SK reinforces its anti-tumor effects by downregulating PYCR1 in HCC cells

2223-

SK,

Non-metabolic enzyme function of PKM2 in hepatocellular carcinoma: A review

in-vitro,

Var,

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,

mice

Necroptosis↑, Shikonin induced necroptosis in osteosarcoma cells
RIP1↑, Shikonin induced necroptosis via upregulating RIP1 and RIP3
RIP3↑,
OS↑, Shikonin prolonged the survival of metastatic disease
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

0.5, 1.0, 2.5, 5.0, or 10.0 μg/mL)

3.52ug/mL

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,

Nine-week-old Wistar rats were administered 6.25, 12.5, and 25 mg/kg/day shikonin orally, one hour after the i.p. injection of 100 mg/kg/day gentamicin for seven days

*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

3044-

SK,

Shikonin Inhibits Non-Small-Cell Lung Cancer H1299 Cell Growth through Survivin Signaling Pathway

in-vitro,

Lung,

H1299

in-vitro,

Lung,

H460

TumCP↓, Results showed that shikonin inhibited the NSCLC H1299 cell proliferation in a dose-dependent manner.
survivin↓, Shikonin also inhibited the mRNA expression and protein level of survivin in H1299 cells
TumCCA↓, Shikonin arrested H1299 cell cycle at the G0/G1 phase by regulating CDK/cyclin family members
CDK2↓,
CDK4↓,
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.
Casp3↑, subsequently regulates the protein expression of XIAP/caspase 3/9, CDK2/4, and cyclin E/D1.
Casp9↑,
cycD1/CCND1↓, downregulated the protein levels of CDK2, CDK4, cyclin E, and cyclin D1
cycE/CCNE↓,

5104-

SK,

Shikonin induces cell cycle arrest in human gastric cancer (AGS) by early growth response 1 (Egr1)-mediated p21 gene expression.

in-vitro,

GC,

AGS

12.5-100 ng/mL dosage of shikonin treatment on AGS cancer cell

TumCP↓, we found that shikonin inhibits cell proliferation by arresting cell cycle progression at the G2/M phase via modulation of p21 in AGS cells.
TumCCA↑,
P21↑, shikonin to induce p21 promoter activity

5103-

SK,

Attenuation of PI3K-Akt-mTOR Pathway to Reduce Cancer Stemness on Chemoresistant Lung Cancer Cells by Shikonin and Synergy with BEZ235 Inhibitor

in-vitro,

NSCLC,

A549

CSCs↓, we found that low doses of shikonin inhibit the proliferation of lung cancer stem-like cells by inhibiting spheroid formation
TumCP↓,
Nanog↓, mRNA level and protein of stemness genes (Nanog and Oct4) were repressed significantly on both sublines.
OCT4↓,
p‑Akt↓, Shikonin reduces the phosphorylated Akt and p70s6k levels, indicating that the PI3K/Akt/mTOR signaling pathway is downregulated by shikonin.
P70S6K↓,
PI3K↓,
mTOR↓,
eff↑, low doses shikonin and dual PI3K-mTOR inhibitor (BEZ235) have a synergistic effect that inhibits the spheroid formation from chemoresistant lung cancer sublines

5102-

SK,

GEM,

Shikonin suppresses tumor growth and synergizes with gemcitabine in a pancreatic cancer xenograft model: Involvement of NF-κB signaling pathway

TumCG↓, shikonin alone significantly suppressed tumor growth and argumented the antitumor activity of gemcitabine.
ChemoSen↑,
NF-kB↓, down-regulation of NF-κB activity and its target genes, decreased proliferation (PCNA and Ki-67)
PCNA↓,
Ki-67↓,
p‑EGFR↓, suppress EGFR phosphorylation [26], generate reactive oxygen species (ROS) [27], [28], arrest the cell cycle through p53 upregulation
ROS↑,
TumCCA↑,
P53↑,
JNK↑, activate the stress-related c-Jun-N-terminal kinase (JNK) pathway [30], and inactivate Akt and NF-κB pathways
Akt↓,

5101-

SK,

Shikonin induces colorectal carcinoma cells apoptosis and autophagy by targeting galectin-1/JNK signaling axis

vitro+vivo,

CRC,

SW-620

vitro+vivo,

CRC,

HCT116

Apoptosis↑, shikonin induced CRC cells apoptosis and autophagy by targeting galectin-1 and JNK signaling pathway both in vitro and in vivo,
TumAuto↑,
Gal1↑, Our results also indicated that shikonin could up-regulate the expression and promote the dimerization of galectin-1
TumCP↓, Shikonin inhibits cell proliferation and induces apoptosis of colorectal cancer cells
ROS↑, Shikonin activates apoptosis and autophagy by upregulating levels of ROS in colorectal cancer cells
eff↑, we overexpressed galectin-1 in SW620 and HCT116 cells and found the two cell lines became more sensitive to shikonin

5100-

SK,

Shikonin-induced necroptosis in nasopharyngeal carcinoma cells via ROS overproduction and upregulation of RIPK1/RIPK3/MLKL expression

vitro+vivo,

NPC,

TumCP↓, Shikonin exhibited a strong inhibitory effect on 5-8F cells in vitro and in vivo
RIP1↑, Moreover, RIPK1, RIPK3, and MLKL were upregulated by shikonin in a dose-dependent manner.
ROS↑, Shikonin induced 5-8F cell death via increased ROS production and the upregulation of RIPK1/RIPK3/MLKL expression, resulting in necroptosis.
Necroptosis↑,
Casp3↑, 7.5 μΜ shikonin significantly increased the activity of caspase-8 (Figure 2A) and caspase-3 (Figure 2B) compared with those of the control
Casp8↑,
eff↓, pretreatment with NAC protected the cells from shikonin mediated cell death.
TumCG↓, nude mice. Shikonin significantly inhibited the growth of the NPC tumors

3051-

SK,

Resveratrol mediates its anti-cancer effects by Nrf2 signaling pathway activation

Review,

Var,

Nrf1↑, Resveratrol is a natural compound that can activate the Nrf2 transcription factor
Apoptosis↑, In different cell lines, resveratrol can increase apoptosis and inhibit the proliferation of cancer cells.
TumCP↓,
eff⇅, But there is a controversy on whether activation of Nrf2 is of clinical benefit in cancer therapy or is a carcinogen?
chemoP↑, chemoprevention effects
eff↑, It has also been suggested that reduction in oxidative conditions in cancer cells may enhance the anticancer effects of antineoplastic drugs [4].
VCAM-1↓, Resveratrol was effective on angiogenesis through an inhibitory direct effect on vascular endothelial growth factor (VEGF) generation and also inhibiting the hypoxia-inducible factor (HIF)-1generation and leads to preventing VEGF secretion
Hif1a↓,

3050-

SK,

Systemic administration of Shikonin ameliorates cognitive impairment and neuron damage in NPSLE mice

in-vivo,

Nor,

mice

*Inflam↓, Shikonin relieved the progression of NPSLE by suppressing neuroinflammation.
*neuroP↑, Shikonin repaired the loss of neuronal synapses in NPSLE mice.
*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,

Fifty-two rats

NA,

Stroke,

*neuroP↑, Shikonin (SK) exerts neuroprotective effects
*p‑PTEN↓, SK administration reversed the upregulation of p-PTEN and the downregulation of p-Akt, p-CREB, and BDNF
*p‑Akt↑,
*Bcl-2↑, SK treatment upregulated the expression of bcl-2 and downregulated the expression of bax, thereby elevating the bcl-2/bax ratio.
*BAX↓,
*cognitive↑, , consequently improving cognitive impairment.
*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,

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
selectivity↑,
EMT↓, shikonin reversed the epithelial-to-mesenchymal transition (EMT) in MDA-MB-231 and 4T1 cells.
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.
TumCI↓,
E-cadherin↑,
N-cadherin↓,
Vim↓,
Snail↓,
β-catenin/ZEB1↓, Shikonin reversed EMT by inhibiting activation of β-catenin signaling through attenuating β-catenin expression
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

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/CCND1↓, 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/CCNE↓,
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.

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

TumCP↓, A549 cells were treated with shikonin for 24 h, 8.0 μM shikonin significantly inhibited cell proliferation,
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.
TumCMig↓,
p‑ERK↓, shikonin repressed the phosphorylation of extracellular signal-regulated kinase (ERK1/2
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

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↑,

2219-

SK,

Shikonin induces apoptosis of HaCaT cells via the mitochondrial, Erk and Akt pathways

in-vitro,

Nor,

HaCaT

 (0–4 µM) for 24 and 48 h

6.34uM@24h

*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

3043-

SK,

Shikonin Induces Apoptosis by Inhibiting Phosphorylation of IGF-1 Receptor in Myeloma Cells.

in-vitro,

Melanoma,

RPMI-8226

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

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,

mice

*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,

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,

Review,

IBD,

Review,

Stroke,

*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↝,

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

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
PDK1↓,
Glycolysis↓, E5 could significantly inhibit the proliferation and aerobic glycolysis of NSCLC cell

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

0-8uM

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

2420-

SK,

Pyruvate kinase M2 regulates mitochondrial homeostasis in cisplatin-induced acute kidney injury

in-vivo,

AKI,

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
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,

Glycolysis↓, Treatment with 5–10 μM of the glycolysis inhibitor shikonin significantly decreased gene expression of the facilitative glucose transporters, GLUT1 and GLUT3
GLUT1↓,
GLUT3↓,
HK2↓, shikonin downregulated expression of the rate-limiting enzymes HK1 and HK2, although a 20 μM dose was needed
HK1↓, HK1
PFK1↓, Shikonin treatment also downregulated the rate-limiting enzyme PFK1
PFK2↓, PFK2 expression was only significantly lowered with a 20 μM dose
PKM2↓, 5 μM shikonin treatment inhibits gene expression of PKM2 (8.59 vs. 2.30, P < 0.001) and downregulated PDK1
lactateProd↓, coupled with decreased lactate production at higher concentrations of shikonin (10 μM and 20 μM)
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

tumCV↓, The results of CCK-8 showed that shikonin significantly inhibited cell viability of HCC cells.
GlucoseCon↓, The levels of glucose uptake and lactate production were dramatically decreased by shikonin-treated.
lactateProd↓,
ChemoSen↑, shikonin enhanced the anti-cancer effect of sorafenib in vitro and in vivo.
PKM2↓, By inhibiting PKM2, shikonin inhibited proliferation and glycolysis and induced cell apoptosis in HCC cells.
Glycolysis↓,

Showing Research Papers: 1 to 50 of 105
Page 1 of 3 JAK&page=2&exSp=open">Next

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 105

Pathway results for Effect on Cancer / Diseased Cells:

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

antiOx↑, 2, Catalase↑, 1, GCLC↑, 1, GPx↑, 1, GSH↑, 3, GSS↑, 1, HO-1↑, 2, MDA↓, 1, MPO↓, 2, NRF2↑, 3, ROS↓, 4, ROS↑, 1, SOD↑, 3, TAC↑, 1,

Mitochondria & Bioenergetics ⓘ

MMP↓, 1,

Core Metabolism/Glycolysis ⓘ

ALAT↓, 1, lactateProd↓, 1, PKM2↓, 2, SIRT1↓, 1,

Cell Death ⓘ

Akt↑, 1, p‑Akt↑, 1, BAX↓, 2, Bcl-2↑, 2, Casp1↓, 1, Casp3↑, 1, iNOS↓, 1, JNK↓, 1, p38↓, 1,

Transcription & Epigenetics ⓘ

other↑, 1,

Protein Folding & ER Stress ⓘ

p‑eIF2α↓, 1,

Proliferation, Differentiation & Cell State ⓘ

ERK↓, 1, PI3K↑, 1, p‑PTEN↓, 1, STAT3↑, 1, TumCG↓, 1,

Angiogenesis & Vasculature ⓘ

NO↓, 1,

Barriers & Transport ⓘ

NHE3↑, 1,

Immune & Inflammatory Signaling ⓘ

AIM2↓, 1, COX2↓, 1, HMGB1↓, 1, IFN-γ↓, 1, p‑IKKα↓, 1, IL18↓, 1, IL1β↓, 2, IL6↓, 1, Inflam↓, 2, NF-kB↓, 1, NF-kB↑, 1, TNF-α↓, 2,

Synaptic & Neurotransmission ⓘ

BDNF↑, 1,

Protein Aggregation ⓘ

NLRP3↓, 1,

Drug Metabolism & Resistance ⓘ

BioAv↓, 1, BioAv↑, 2, eff↑, 1, Half-Life↝, 1,

Clinical Biomarkers ⓘ

ALAT↓, 1, AST↓, 1, IL6↓, 1,

Functional Outcomes ⓘ

cognitive↑, 2, hepatoP↑, 1, motorD↑, 1, neuroP↑, 3, RenoP↑, 1, toxicity∅, 1,

Infection & Microbiome ⓘ

Sepsis↓, 1,
Total Targets: 65

Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells

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

Shikonin Cancer Research Results

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Transcription & Epigenetics ⓘ

Protein Folding & ER Stress ⓘ

Autophagy & Lysosomes ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Cellular Microenvironment ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Transcription & Epigenetics ⓘ

Protein Folding & ER Stress ⓘ

Proliferation, Differentiation & Cell State ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Synaptic & Neurotransmission ⓘ

Protein Aggregation ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Infection & Microbiome ⓘ

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