Shikonin / Apoptosis 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)


Apoptosis, Apoptosis: Click to Expand ⟱
Source:
Type: type of cell death
Situation in which a cell actively pursues a course toward death upon receiving certain stimuli.
Cancer is one of the scenarios where too little apoptosis occurs, resulting in malignant cells that will not die.
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
tumCV↓, TumCMig↓, TumCI↓, TumAuto↑, Apoptosis↑, Bcl-2↓, BAX↑, cl‑Casp3↑, cl‑Casp8↑, cl‑PARP↑, AMPK↑, mTOR↑, TumVol↓, OS↑, LC3I↑,
2360- SK,    Shikonin inhibits growth, invasion and glycolysis of nasopharyngeal carcinoma cells through inactivating the phosphatidylinositol 3 kinase/AKT signal pathway
- in-vitro, NPC, HONE1 - in-vitro, NPC, SUNE-1
TumCP↓, Apoptosis↑, TumCMig↓, TumCI↓, GlucoseCon↓, lactateProd↓, ATP↓, PKM2↓, PI3K↓, Akt↓, MMP3↓, MMP9↓, TIMP1↑,
2355- SK,    Pharmacological properties and derivatives of shikonin-A review in recent years
- Review, Var, NA
AntiCan↑, TumCP↓, TumCMig↓, Apoptosis↑, TumAuto↑, Necroptosis↑, ROS↑, TrxR1↓, PKM2↓, RIP1↓, RIP3↓, Src↓, FAK↓, PI3K↓, Akt↓, mTOR↓, GRP58↓, MMPs↓, ATF2↓, cl‑PARP↑, Casp3↑, p‑p38↑, p‑JNK↑, p‑ERK↓,
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
Apoptosis↑, ER Stress↑, PERK↑, eIF2α↑, CHOP↑, mt-Ca+2↑, MMP↓, Bcl-2↓, Casp3↑, Casp9↑, ERK↑, JNK↑, p38↓,
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 - in-vitro, CRC, HCT15 - in-vivo, NA, NA
Apoptosis↑, Bcl-2↓, Casp3↑, Casp9↑, cl‑PARP↑, GRP78/BiP↑, PERK↑, eIF2α↑, ATF4↑, CHOP↑, JNK↑, eff↓, ER Stress↑, ROS↑, TumCG↓,
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↑, TumCP↓, tumCV↓, Necroptosis↑, P53↑, ROS↑, NF-kB↓,
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↑,
3051- SK,    Resveratrol mediates its anti-cancer effects by Nrf2 signaling pathway activation
- Review, Var, NA
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↓,
3043- SK,    Apoptosis-by-Inhibiting">Shikonin Induces Apoptosis by Inhibiting Phosphorylation of IGF-1 Receptor in Myeloma Cells.
- in-vitro, Melanoma, RPMI-8226
IGF-1↓, Apoptosis↑, TumCCA↑, MMP↓, Casp3↑, P53↑, BAX↑, Mcl-1↓, EGFR↓, Src↑, KDR/FLK-1↓, p‑IGF-1↓, PI3K↓, Akt↓,
3040- SK,    Pharmacological Properties of Shikonin – A Review of Literature since 2002
- Review, Var, NA - Review, IBD, NA - Review, Stroke, NA
*Half-Life↝, *BioAv↓, *BioAv↑, *BioAv↑, *Inflam↓, *TNF-α↓, *other↑, *MPO↓, *COX2↓, *NF-kB↑, *STAT3↑, *antiOx↑, *ROS↓, *neuroP↑, *SOD↑, *Catalase↑, *GPx↑, *Bcl-2↑, *BAX↓, cardioP↑, AntiCan↑, NF-kB↓, ROS↑, PKM2↓, TumCCA↑, Necroptosis↑, Apoptosis↑, DNAdam↑, MMP↓, Cyt‑c↑, 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↑, Pyro↑, Casp↑, cl‑PARP↑, GSDME↑, ROS↑, COX2↓, PDK1↓, Akt↓, ERK↓, eff↓, eff↓, eff↑,
1346- SK,    An Oxidative Stress Mechanism of Shikonin in Human Glioma Cells
- in-vitro, GBM, U87MG - in-vitro, GBM, Hs683
NRF2↓, ROS↑, Apoptosis↑, Cyt‑c↑, GSH↓, MMP↓, P53↑, HO-1⇅,
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↓,
2182- SK,  Cisplatin,    Shikonin inhibited glycolysis and sensitized cisplatin treatment in non-small cell lung cancer cells via the exosomal pyruvate kinase M2 pathway
- in-vitro, Lung, A549 - in-vitro, Lung, PC9 - in-vivo, NA, NA
tumCV↓, TumCP↓, TumCI↓, TumCMig↓, Apoptosis↑, PKM2↓, Glycolysis↓, GlucoseCon↓, lactateProd↓, ChemoSen↑, TumVol↓, TumW↓, GLUT1↓,
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↓, selectivity↑, Casp↑, PARP↑, Apoptosis↑, ROS↑, eff↓, selectivity↑,
2188- SK,    Molecular mechanism of shikonin inhibiting tumor growth and potential application in cancer treatment
- Review, Var, NA
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↓,
1312- SK,    Shikonin induces apoptosis through reactive oxygen species/extracellular signal-regulated kinase pathway in osteosarcoma cells
- in-vitro, OS, 143B
ROS↑, p‑ERK↑, Bcl-2↓, cl‑PARP↑, Apoptosis↑, TumCCA↑, Bcl-2↑, proCasp3↓,
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↓, TumCP↓, Apoptosis↑, ChemoSen↑, ROS↑,
2194- SK,    Efficacy of Shikonin against Esophageal Cancer Cells and its possible mechanisms in vitro and in vivo
- in-vitro, ESCC, Eca109 - in-vitro, ESCC, EC9706 - in-vivo, NA, NA
tumCV↓, TumCCA↑, Apoptosis↑, EGFR↓, PI3K↓, Hif1a↓, PKM2↓, cycD1/CCND1↓, AntiTum↑,
2190- SK,    Shikonin exerts antitumor activity by causing mitochondrial dysfunction in hepatocellular carcinoma through PKM2-AMPK-PGC1α signaling pathway
- in-vitro, HCC, HCCLM3
TumCP↓, TumCMig↓, TumCI↓, Apoptosis↑, MMP↓, ROS↑, OCR↓, ATP↓, PKM2↓,

Showing Research Papers: 1 to 22 of 22

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 22

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

GSH↓, 2,   HO-1⇅, 1,   Nrf1↑, 1,   NRF2↓, 1,   OXPHOS⇅, 1,   ROS↑, 15,   TrxR1↓, 1,  

Mitochondria & Bioenergetics ⓘ

ATP↓, 2,   MMP↓, 6,   OCR↓, 1,  

Core Metabolism/Glycolysis ⓘ

AMPK↑, 1,   GlucoseCon↓, 2,   Glycolysis↓, 2,   lactateProd↓, 2,   LDH↝, 1,   PDK1↓, 1,   PKM2↓, 7,   SIRT1↑, 1,  

Cell Death ⓘ

Akt↓, 5,   Apoptosis↑, 22,   ATF2↓, 1,   BAX↑, 2,   Bcl-2↓, 4,   Bcl-2↑, 1,   Casp↑, 2,   Casp3↑, 5,   cl‑Casp3↑, 2,   proCasp3↓, 1,   proCasp3↑, 1,   cl‑Casp8↑, 1,   Casp9↑, 2,   Cyt‑c↑, 2,   GRP58↓, 1,   GSDME↑, 1,   JNK↑, 2,   p‑JNK↑, 1,   Mcl-1↓, 1,   Necroptosis↑, 4,   p38↓, 1,   p38↑, 2,   p‑p38↑, 1,   Pyro↑, 1,   RIP1↓, 1,   RIP1↑, 1,  

Transcription & Epigenetics ⓘ

tumCV↓, 4,  

Protein Folding & ER Stress ⓘ

CHOP↑, 3,   eIF2α↑, 2,   p‑eIF2α↑, 2,   ER Stress↑, 3,   GRP78/BiP↑, 1,   PERK↑, 2,  

Autophagy & Lysosomes ⓘ

Beclin-1↑, 1,   LC3B-II↑, 1,   LC3I↑, 1,   TumAuto↑, 4,  

DNA Damage & Repair ⓘ

DNAdam↑, 1,   P53↑, 3,   PARP↑, 1,   cl‑PARP↑, 6,  

Cell Cycle & Senescence ⓘ

cycD1/CCND1↓, 3,   cycE/CCNE↓, 1,   P21↑, 1,   TumCCA↑, 6,  

Proliferation, Differentiation & Cell State ⓘ

ERK↓, 2,   ERK↑, 1,   p‑ERK↓, 1,   p‑ERK↑, 1,   FOXO3↑, 1,   IGF-1↓, 1,   p‑IGF-1↓, 1,   mTOR↓, 1,   mTOR↑, 1,   PI3K↓, 5,   Src↓, 1,   Src↑, 1,   p‑STAT3↓, 1,   TumCG↓, 2,  

Migration ⓘ

Ca+2↓, 1,   mt-Ca+2↑, 1,   FAK↓, 1,   MMP3↓, 1,   MMP9↓, 1,   MMPs↓, 1,   PAK1↓, 1,   RIP3↓, 1,   RIP3↑, 1,   TIMP1↑, 1,   TumCI↓, 4,   TumCMig↓, 5,   TumCP↓, 9,   VCAM-1↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   ATF4↑, 1,   EGFR↓, 4,   EGR1↑, 1,   Hif1a↓, 2,   KDR/FLK-1↓, 1,   VEGF↓, 1,  

Barriers & Transport ⓘ

GLUT1↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   Gal1↑, 1,   IL6↓, 1,   JAK1?, 1,   p‑JAK1↓, 1,   p‑JAK2↓, 1,   NF-kB↓, 3,  

Cellular Microenvironment ⓘ

ADAM17↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 1,   ChemoSen↑, 2,   eff↓, 8,   eff↑, 3,   eff⇅, 1,   Half-Life↓, 1,   selectivity↑, 2,  

Clinical Biomarkers ⓘ

EGFR↓, 4,   IL6↓, 1,   LDH↝, 1,  

Functional Outcomes ⓘ

AntiCan↑, 2,   AntiTum↑, 1,   cardioP↑, 1,   chemoP↑, 1,   OS↑, 1,   TumVol↓, 2,   TumW↓, 1,  
Total Targets: 124

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 1,   Catalase↑, 1,   GPx↑, 1,   MPO↓, 1,   ROS↓, 1,   SOD↑, 1,  

Cell Death ⓘ

BAX↓, 1,   Bcl-2↑, 1,  

Transcription & Epigenetics ⓘ

other↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

STAT3↑, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   Inflam↓, 1,   NF-kB↑, 1,   TNF-α↓, 1,  

Drug Metabolism & Resistance ⓘ

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

Functional Outcomes ⓘ

neuroP↑, 1,  
Total Targets: 18

Scientific Paper Hit Count for: Apoptosis, Apoptosis
22 Shikonin
1 Cisplatin
1 Chemotherapy
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#:14  State#:%  Dir#:2
  wNotes=0  sortOrder:rid,rpid

 

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