Shikonin / IL6 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↓, IL6↓">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)


IL6, Interleukin-6: Click to Expand ⟱
Source: HalifaxProj(inhibit)
Type:
Interleukin-6 (IL-6) is a cytokine that plays a significant role in inflammation and the immune response. It is produced by various cell types, including T cells, B cells, macrophages, and fibroblasts.
IL-6 can promote tumor cell proliferation and survival. Many cancer cells produce IL-6, which can create an autocrine loop that supports their growth.
IL-6 is a high-value inflammatory biomarker in cancer, reporting cytokine burden, catabolic stress, and STAT3-linked survival signaling. While not tumor-specific, elevated and rising IL-6 strongly predicts poor prognosis and limited treatment tolerance, making it an important system-state indicator alongside CRP and ferritin.


Scientific Papers found: Click to Expand⟱
2361- SK,    Natural shikonin and acetyl-shikonin improve intestinal microbial and protein composition to alleviate colitis-associated colorectal cancer
- in-vivo, CRC, NA
GutMicro↑, Dose↝, IL1β↓, IL6↓, TNF-α↓, PKM2↓,
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↓,
3042- SK,    The protective effects of Shikonin on lipopolysaccharide/D -galactosamine-induced acute liver injury via inhibiting MAPK and NF-kB and activating Nrf2/HO-1 signaling pathways
- in-vivo, Nor, NA
*TNF-α↓, *IL1β↓, *IL6↓, *IFN-γ↓, *ALAT↓, *AST↓, *MPO↓, *ROS↓, *JNK↓, *ERK↓, *p38↓, *NF-kB↓, *p‑IKKα↓, *SOD↑, *GSH↑, *HO-1↑, *NRF2↑, *hepatoP↑,
2415- SK,    Shikonin induces programmed death of fibroblast synovial cells in rheumatoid arthritis by inhibiting energy pathways
- in-vivo, Arthritis, NA
Apoptosis?, TumAuto↑, ROS↑, ATP↓, Glycolysis↓, PI3K↓, Akt↓, mTOR↓, *Apoptosis↓, *Inflam↓, *TNF-α↓, *IL6↓, *IL8↓, *IL10↓, *IL17↓, *hepatoP↑, *RenoP↑, PKM2↓, GLUT1↓, HK2↓,
1049- SK,    Shikonin inhibits immune checkpoint PD-L1 expression on macrophage in sepsis by modulating PKM2
- in-vivo, NA, NA
TNF-α↓, IL6↓, IFN-γ↓, IL1β↓, PD-L1↓, p‑PKM2↓,
2201- SK,    Shikonin promotes ferroptosis in HaCaT cells through Nrf2 and alleviates imiquimod-induced psoriasis in mice
- in-vitro, PSA, HaCaT - in-vivo, NA, NA
*eff↑, *IL6↓, *IL17↓, *TNF-α↓, *lipid-P↑, *NRF2↓, *HO-1↝, *NCOA4↝, *GPx4↓, *Ferroptosis↓, *Inflam↓, *ROS↓, *Iron↓,
2218- SK,    Shikonin Alleviates Endothelial Cell Injury Induced by ox-LDL via AMPK/Nrf2/HO-1 Signaling Pathway
- in-vitro, Nor, HUVECs
*Dose↝, *Apoptosis↓, *Casp3↓, *Bcl-2↑, *Inflam↓, *VCAM-1↓, *ICAM-1↓, *E-sel↓, *ROS↓, *SOD↑, *AMPK↑, *NRF2↑, *HO-1↑, *TNF-α↓, *IL1β↓, *IL6↓,
2213- SK,    Shikonin attenuates cerebral ischemia/reperfusion injury via inhibiting NOD2/RIP2/NF-κB-mediated microglia polarization and neuroinflammation
- in-vivo, Stroke, NA
*neuroP↑, *Inflam↓, *iNOS↓, *TNF-α↓, *IL1β↓, *IL6↓, *ARG↑, *TGF-β↑, *IL10↑, *NF-kB↓, *eff↓,

Showing Research Papers: 1 to 8 of 8

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 8

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

ROS↑, 2,  

Mitochondria & Bioenergetics ⓘ

ATP↓, 1,  

Core Metabolism/Glycolysis ⓘ

Glycolysis↓, 1,   HK2↓, 1,   PKM2↓, 2,   p‑PKM2↓, 1,  

Cell Death ⓘ

Akt↓, 1,   Apoptosis?, 1,   Apoptosis↑, 1,   Casp3↑, 1,  

Protein Folding & ER Stress ⓘ

p‑eIF2α↑, 1,  

Autophagy & Lysosomes ⓘ

TumAuto↑, 1,  

DNA Damage & Repair ⓘ

cl‑PARP↑, 1,  

Cell Cycle & Senescence ⓘ

cycD1/CCND1↓, 1,   cycE/CCNE↓, 1,   TumCCA↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

mTOR↓, 1,   PI3K↓, 1,   p‑STAT3↓, 1,   TumCG↓, 1,  

Barriers & Transport ⓘ

GLUT1↓, 1,  

Immune & Inflammatory Signaling ⓘ

IFN-γ↓, 1,   IL1β↓, 2,   IL6↓, 3,   JAK1?, 1,   p‑JAK1↓, 1,   p‑JAK2↓, 1,   PD-L1↓, 1,   TNF-α↓, 2,  

Cellular Microenvironment ⓘ

ADAM17↓, 1,  

Drug Metabolism & Resistance ⓘ

Dose↝, 1,   eff↓, 1,  

Clinical Biomarkers ⓘ

GutMicro↑, 1,   IL6↓, 3,   PD-L1↓, 1,  
Total Targets: 35

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

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

Metal & Cofactor Biology ⓘ

NCOA4↝, 1,  

Core Metabolism/Glycolysis ⓘ

ALAT↓, 1,   AMPK↑, 1,  

Cell Death ⓘ

Apoptosis↓, 2,   Bcl-2↑, 1,   Casp3↓, 1,   Ferroptosis↓, 1,   iNOS↓, 1,   JNK↓, 1,   p38↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

ERK↓, 1,  

Migration ⓘ

ARG↑, 1,   E-sel↓, 1,   TGF-β↑, 1,   VCAM-1↓, 1,  

Immune & Inflammatory Signaling ⓘ

ICAM-1↓, 1,   IFN-γ↓, 1,   p‑IKKα↓, 1,   IL10↓, 1,   IL10↑, 1,   IL17↓, 2,   IL1β↓, 3,   IL6↓, 5,   IL8↓, 1,   Inflam↓, 4,   NF-kB↓, 2,   TNF-α↓, 5,  

Drug Metabolism & Resistance ⓘ

Dose↝, 1,   eff↓, 1,   eff↑, 1,  

Clinical Biomarkers ⓘ

ALAT↓, 1,   AST↓, 1,   IL6↓, 5,  

Functional Outcomes ⓘ

hepatoP↑, 2,   neuroP↑, 1,   RenoP↑, 1,  
Total Targets: 48

Scientific Paper Hit Count for: IL6, Interleukin-6
8 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#:158  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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