Shikonin / RIP3 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)


RIP3, Receptor‐Interacting Protein Kinase 3: Click to Expand ⟱
Source:
Type:
RIP3 Receptor‐Interacting Protein Kinase 3
Several cancers have decreased RIP3 expression and is associated with poorer prognosis, more aggressive tumor behavior, and resistance to chemotherapies. Restoration of RIP3 may promote necroptosis, providing a potential mechanism to overcome therapy resistance.
Scientific Papers found: Click to Expand⟱
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↑, RIP3↑, Glycolysis↓, G6PD↓, HK2↓, PKM2↓, H2O2↑, GSH↓, ROS↑,
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↓,
2222- SK,    The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis
- in-vitro, OS, U2OS - in-vitro, OS, 143B - in-vivo, NA, NA
Necroptosis↑, RIP1↑, RIP3↑, OS↑, P53↑,
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↓,
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↑, ROS↑, GSH↓,
2197- SK,    Shikonin derivatives for cancer prevention and therapy
- Review, Var, NA
ROS↑, Ca+2↑, BAX↑, Bcl-2↓, MMP9↓, NF-kB↓, PKM2↓, 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↑,

Showing Research Papers: 1 to 6 of 6

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 6

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

GSH↓, 3,   H2O2↑, 1,   NRF2↓, 1,   ROS↑, 5,   TrxR1↓, 1,  

Mitochondria & Bioenergetics ⓘ

MMP↓, 1,  

Core Metabolism/Glycolysis ⓘ

G6PD↓, 1,   Glycolysis↓, 1,   HK2↓, 1,   PKM2↓, 3,   SIRT1↑, 1,  

Cell Death ⓘ

Akt↓, 2,   Apoptosis↑, 2,   ATF2↓, 1,   BAX↑, 1,   Bcl-2↓, 1,   Casp3↑, 2,   proCasp3↑, 1,   Casp7↑, 1,   Casp9↑, 1,   GRP58↓, 1,   p‑JNK↑, 1,   Myc↓, 1,   Necroptosis↑, 3,   p38↑, 1,   p‑p38↑, 1,   RIP1↓, 1,   RIP1↑, 5,   TRAIL↑, 1,  

Autophagy & Lysosomes ⓘ

TumAuto↑, 1,  

DNA Damage & Repair ⓘ

DFF45↓, 1,   DNAdam↑, 1,   DNMT1↓, 1,   P53↑, 2,   cl‑PARP↑, 1,  

Cell Cycle & Senescence ⓘ

P21↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

EMT↓, 1,   ERK↓, 1,   p‑ERK↓, 1,   FOXO3↑, 1,   mTOR↓, 2,   PI3K↓, 2,   PTEN↑, 1,   Src↓, 2,  

Migration ⓘ

Ca+2↓, 1,   Ca+2↑, 1,   FAK↓, 2,   MMP13↓, 1,   MMP7↓, 1,   MMP9↓, 1,   MMPs↓, 1,   RIP3↓, 1,   RIP3↑, 5,   TumCMig↓, 1,   TumCP↓, 1,   uPA↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   EGFR↓, 1,   EGR1↑, 1,   Hif1a↓, 1,   VEGF↓, 2,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   NF-kB↓, 2,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 1,   eff↓, 1,   Half-Life↓, 1,   MDR1↓, 1,   RadioS↑, 1,  

Clinical Biomarkers ⓘ

AR↓, 1,   EGFR↓, 1,   Myc↓, 1,  

Functional Outcomes ⓘ

AntiCan↑, 1,   OS↑, 1,  
Total Targets: 74

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: RIP3, Receptor‐Interacting Protein Kinase 3
6 Shikonin
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#:1066  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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