Shikonin / eff 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↓, 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)

eff, efficacy: Click to Expand ⟱

Source:

Type:

Power to enhance an anti cancer effect

Scientific Papers found: Click to Expand⟱

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↑, lactateProd↓, PKM2↓,

2358-

SK,

SIRT1 improves lactate homeostasis in the brain to alleviate parkinsonism via deacetylation and inhibition of PKM2

in-vivo,

Park,

mice

*eff↑, *PKM2↓, *motorD↑, *lactateProd↓,

2230-

SK,

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

in-vitro,

CRC,

HCT116

in-vivo,

NA,

TumCG↓, Bcl-2↓, ROS↑, Bcl-xL↓, MMP↓, Casp↑, selectivity↑, cycD1/CCND1↓, TumCCA↑, eff↓,

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↑, TumAuto↑, TumCP↓, TumCCA↑, P21↑, cycD1/CCND1↓, ER Stress↑, p‑eIF2α↑, CHOP↑, cl‑Casp3↑, p38↑, LC3B-II↑, Beclin-1↑, ROS↑, eff↓,

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↑, Bcl-2↓, Casp3↑, Casp9↑, cl‑PARP↑, GRP78/BiP↑, PERK↑, eIF2α↑, ATF4↑, CHOP↑, JNK↑, eff↓, ER Stress↑, ROS↑, TumCG↓,

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↑, TumCP↓, TumCD↑, ROS↑, MMP↓, Casp↑, Cyt‑c↑, Endon↑, AIF↑, eff↓, ChemoSen↑, TumCCA↑, GSH/GSSG↓, lipid-P↑,

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↑, ROS↑, eff↓, Akt↓, RIP1↓, NF-kB↓,

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↓, PI3K↓, Akt↓, mTOR↓, eff↑,

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↓, TumCP↓, Nanog↓, OCT4↓, p‑Akt↓, P70S6K↓, PI3K↓, mTOR↓, eff↑,

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↑, TumAuto↑, Gal1↑, TumCP↓, ROS↑, eff↑,

5100-

SK,

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

vitro+vivo,

NPC,

TumCP↓, RIP1↑, ROS↑, Necroptosis↑, Casp3↑, Casp8↑, eff↓, TumCG↓,

3051-

SK,

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

Review,

Var,

Nrf1↑, Apoptosis↑, TumCP↓, eff⇅, chemoP↑, eff↑, VCAM-1↓, Hif1a↓,

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↓, p‑STAT3↓, ADAM17↓, Apoptosis↑, Casp3↑, cl‑PARP↑, cycD1/CCND1↓, cycE/CCNE↓, TumCCA↑, JAK1?, p‑JAK1↓, p‑JAK2↓, p‑eIF2α↑, eff↓, ROS↑, IL6↓,

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↑, Pyro↑, Casp↑, cl‑PARP↑, GSDME↑, ROS↑, COX2↓, PDK1↓, Akt↓, ERK↓, eff↓, eff↓, eff↑,

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↓, PKM2↓, Apoptosis↑, ROS↑, OXPHOS⇅, eff↓,

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

2.6uM

in-vitro,

Lung,

H1650

3.9uM

in-vitro,

Nor,

CCD19

12.2uM

Normal cells, shows selectivity

EGFR↓, selectivity↑, Casp↑, PARP↑, Apoptosis↑, ROS↑, eff↓, selectivity↑,

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,

TumCG↓, selectivity↑, *toxicity∅, Necroptosis↑, ROS↑, p62↑, Keap1↑, *NRF2↑, eff↑,

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,

mice

ChemoSen↑, selectivity↑, i-ROS↑, DNAdam↑, MMP↓, TumCCA↑, eff↓, *toxicity↓,

2188-

SK,

Molecular mechanism of shikonin inhibiting tumor growth and potential application in cancer treatment

Review,

Var,

ROS↑, EGFR↓, PI3K↓, Akt↓, angioG↓, Apoptosis↑, Necroptosis↑, GSH↓, Ca+2↓, MMP↓, ERK↓, p38↑, proCasp3↑, eff↓, VEGF↓, FOXO3↑, EGR1↑, SIRT1↑, RIP1↑, RIP3↑, BioAv↓, NF-kB↓, Half-Life↓,

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↑, cl‑PARP↑, Catalase↓, SOD1↑, Bcl-2↓, BAX↑, eff↓,

1281-

SK,

Enhancement of NK cells proliferation and function by Shikonin

in-vivo,

Colon,

Caco-2

mice

Perforin↑, GranB↑, p‑ERK↑, p‑Akt↑, NK cell↑, eff↝,

2201-

SK,

Shikonin promotes ferroptosis in HaCaT cells through Nrf2 and alleviates imiquimod-induced psoriasis in mice

in-vitro,

PSA,

HaCaT

in-vivo,

NA,

mice

*eff↑, *IL6↓, *IL17↓, *TNF-α↓, *lipid-P↑, *NRF2↓, *HO-1↝, *NCOA4↝, *GPx4↓, *Ferroptosis↓, *Inflam↓, *ROS↓, *Iron↓,

2217-

SK,

Shikonin Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis to Attenuate Renal Ischemia/Reperfusion Injury by Activating the Sirt1/Nrf2/HO-1 Pathway

in-vivo,

Nor,

mice

in-vitro,

Nor,

HK-2

*ER Stress↓, *SIRT1↑, *NRF2↑, *HO-1↑, *eff↓, *RenoP↑, *GRP78/BiP↓, *CHOP↓, *Casp12↓, *BAX↓, *cl‑Casp3↓,

2215-

SK,

doxoR,

Shikonin alleviates doxorubicin-induced cardiotoxicity via Mst1/Nrf2 pathway in mice

in-vivo,

Nor,

mice

*cardioP↑, *ROS↓, *Inflam↓, *Mst1↓, *NRF2↑, *eff↓, *antiOx↑, *SOD↑, *GSH↑, *TNF-α↓, BAX↓, Bcl-2↑,

2213-

SK,

Shikonin attenuates cerebral ischemia/reperfusion injury via inhibiting NOD2/RIP2/NF-κB-mediated microglia polarization and neuroinflammation

in-vivo,

Stroke,

 MCAO/R rats

*neuroP↑, *Inflam↓, *iNOS↓, *TNF-α↓, *IL1β↓, *IL6↓, *ARG↑, *TGF-β↑, *IL10↑, *NF-kB↓, *eff↓,

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

1.854 μm

TumCA↓, TumCI↓, TumCMig↓, MMP2↓, MMP7↓, TLR2↓, p65↓, NF-kB↓, eff↑, ROS↑,

2196-

SK,

Research progress in mechanism of anticancer action of shikonin targeting reactive oxygen species

Review,

Var,

*ALAT↓, *AST↓, *Inflam?, *EMT↑, ROS?, TrxR1↓, PERK↑, eIF2α↑, ATF4↑, CHOP↑, IRE1↑, JNK↑, eff↝, DR5↑, Glycolysis↓, PKM2↓, ChemoSen↑, GPx4↓, HO-1↑,

2189-

SK,

PKM2 inhibitor shikonin suppresses TPA-induced mitochondrial malfunction and proliferation of skin epidermal JB6 cells

in-vitro,

Melanoma,

PKM2↓, chemoPv↑, eff↝, lactateProd↓, ROS↑, *ROS?, *PKM2↓,

Showing Research Papers: 1 to 28 of 28

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 28

Pathway results for Effect on Cancer / Diseased Cells:

Functional Outcomes ⓘ

chemoP↑, 1, chemoPv↑, 1,
Total Targets: 118

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

antiOx↑, 1, Ferroptosis↓, 1, GPx4↓, 1, GSH↑, 1, HO-1↑, 1, HO-1↝, 1, Iron↓, 1, lipid-P↑, 1, NRF2↓, 1, NRF2↑, 3, ROS?, 1, ROS↓, 2, SOD↑, 1,

Metal & Cofactor Biology ⓘ

NCOA4↝, 1,

Core Metabolism/Glycolysis ⓘ

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

Cell Death ⓘ

BAX↓, 1, Casp12↓, 1, cl‑Casp3↓, 1, Ferroptosis↓, 1, iNOS↓, 1,

Protein Folding & ER Stress ⓘ

CHOP↓, 1, ER Stress↓, 1, GRP78/BiP↓, 1,

Proliferation, Differentiation & Cell State ⓘ

EMT↑, 1, Mst1↓, 1,

Migration ⓘ

ARG↑, 1, TGF-β↑, 1,

Immune & Inflammatory Signaling ⓘ

IL10↑, 1, IL17↓, 1, IL1β↓, 1, IL6↓, 2, Inflam?, 1, Inflam↓, 3, NF-kB↓, 1, TNF-α↓, 3,

Drug Metabolism & Resistance ⓘ

eff↓, 3, eff↑, 2,

Clinical Biomarkers ⓘ

ALAT↓, 1, AST↓, 1, IL6↓, 2,

Functional Outcomes ⓘ

cardioP↑, 1, motorD↑, 1, neuroP↑, 1, RenoP↑, 1, toxicity↓, 1, toxicity∅, 1,
Total Targets: 49

Scientific Paper Hit Count for: eff, efficacy

28 Shikonin
1 Cisplatin
1 doxorubicin

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#:961  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

Shikonin / eff Cancer Research Results

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Protein Folding & ER Stress ⓘ

Autophagy & Lysosomes ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Immune & Inflammatory Signaling ⓘ

Cellular Microenvironment ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Metal & Cofactor Biology ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Protein Folding & ER Stress ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

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