Shikonin / Casp9 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)


Casp9, Caspase-9: Click to Expand ⟱
Source:
Type:
Caspase-9 is the apoptotic initiator protease of the intrinsic or mitochondrial apoptotic pathway, which is activated at multi-protein activation platforms.
Caspases are divided into two groups: the initiator caspases (caspase-2, -8, -9 and -10), which are the first to be activated in response to a signal, and the executioner caspases (caspase-3, -6, and -7) that carry out the demolition phase of apoptosis.
Caspase-9:
Role: Initiator caspase in the intrinsic apoptotic pathway.
Cancers: Frequently studied in leukemia and solid tumors.
Prognosis: Reduced expression is often linked to chemoresistance and poor prognosis.
Scientific Papers found: Click to Expand⟱
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↓,
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↓,
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↓, survivin↓, TumCCA↓, CDK2↓, CDK4↓, XIAP↓, Casp3↑, Casp9↑, cycD1/CCND1↓, cycE/CCNE↓,
2007- SK,    Shikonin Directly Targets Mitochondria and Causes Mitochondrial Dysfunction in Cancer Cells
- in-vitro, lymphoma, U937 - in-vitro, BC, MCF-7 - in-vitro, BC, SkBr3 - in-vitro, CRC, HCT116 - in-vitro, OS, U2OS - NA, Nor, RPE-1
tumCV↓, selectivity↑, Dose↝, other↑, MMP↓, ROS↑, DNAdam↑, Ca+2↑, Casp9↑, Cyt‑c↑, *toxicity↓,
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 5 of 5

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 5

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

NRF2↓, 1,   ROS↑, 3,  

Mitochondria & Bioenergetics ⓘ

MMP↓, 2,   XIAP↓, 1,  

Core Metabolism/Glycolysis ⓘ

PKM2↓, 1,  

Cell Death ⓘ

Apoptosis↑, 2,   BAX↑, 1,   Bcl-2↓, 3,   Casp3↑, 4,   Casp7↑, 1,   Casp9↑, 5,   Cyt‑c↑, 1,   JNK↑, 2,   Myc↓, 1,   p38↓, 1,   RIP1↑, 1,   survivin↓, 1,   TRAIL↑, 1,  

Transcription & Epigenetics ⓘ

other↑, 1,   tumCV↓, 1,  

Protein Folding & ER Stress ⓘ

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

DNA Damage & Repair ⓘ

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

Cell Cycle & Senescence ⓘ

CDK2↓, 1,   CDK4↓, 1,   cycD1/CCND1↓, 1,   cycE/CCNE↓, 1,   P21↓, 1,   TumCCA↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

EMT↓, 1,   ERK↑, 1,   mTOR↓, 1,   PTEN↑, 1,   Src↓, 1,   TumCG↓, 1,  

Migration ⓘ

Ca+2↑, 2,   mt-Ca+2↑, 1,   FAK↓, 1,   MMP13↓, 1,   MMP7↓, 1,   MMP9↓, 1,   RIP3↑, 1,   TumCP↓, 1,   uPA↓, 1,  

Angiogenesis & Vasculature ⓘ

ATF4↑, 1,   Hif1a↓, 1,   VEGF↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   NF-kB↓, 1,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 1,  

Drug Metabolism & Resistance ⓘ

Dose↝, 1,   eff↓, 1,   MDR1↓, 1,   RadioS↑, 1,   selectivity↑, 1,  

Clinical Biomarkers ⓘ

AR↓, 1,   Myc↓, 1,  
Total Targets: 64

Pathway results for Effect on Normal Cells:


Functional Outcomes ⓘ

toxicity↓, 1,  
Total Targets: 1

Scientific Paper Hit Count for: Casp9, Caspase-9
5 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#:45  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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