Shikonin / PFK2 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)

PFK2, PFK2: Click to Expand ⟱

Source:

Type:

“PFK-2” typically refers to the family of bifunctional enzymes (commonly known as 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases or PFKFBs) that regulate the levels of fructose-2,6-bisphosphate—a critical allosteric activator of glycolysis.

– PFK-2 enzymes catalyze the synthesis of fructose-2,6-bisphosphate (F2,6BP), which in turn is a potent activator of phosphofructokinase-1 (PFK-1), a key rate-limiting enzyme in glycolysis.
– Increased activity of PFK-2 contributes to enhanced glycolysis and the diversion of glycolytic intermediates into biosynthetic pathways that support rapid tumor cell growth and proliferation. – Upregulated glycolysis supports not only energy production but also the generation of precursors needed for nucleotide, amino acid, and lipid synthesis, aiding tumor progression.

– Elevated expression of certain PFK-2 isoforms (notably PFKFB3) has been observed in various cancers such as breast, colorectal, lung, and others.
– High PFK-2 expression is frequently associated with increased glycolytic activity, enhanced cell proliferation, and a shift toward an anabolic phenotype, correlating with more aggressive tumor behavior.

Scientific Papers found: Click to Expand⟱

2419-

SK,

Regulation of glycolysis and the Warburg effect in wound healing

in-vivo,

Nor,

Glycolysis↓, GLUT1↓, GLUT3↓, HK2↓, HK1↓, PFK1↓, PFK2↓, PKM2↓, lactateProd↓, GlucoseCon↓,

Showing Research Papers: 1 to 1 of 1

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

HK1↓, 1,

Core Metabolism/Glycolysis ⓘ

GlucoseCon↓, 1, Glycolysis↓, 1, HK2↓, 1, lactateProd↓, 1, PFK1↓, 1, PFK2↓, 1, PKM2↓, 1,

Barriers & Transport ⓘ

GLUT1↓, 1, GLUT3↓, 1,
Total Targets: 10

Pathway results for Effect on Normal Cells:

Total Targets: 0

Scientific Paper Hit Count for: PFK2, PFK2

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