Shikonin / TumCCA 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)

TumCCA, Tumor cell cycle arrest: Click to Expand ⟱

Source:

Type:

Tumor cell cycle arrest refers to the process by which cancer cells stop progressing through the cell cycle, which is the series of phases that a cell goes through to divide and replicate. This arrest can occur at various checkpoints in the cell cycle, including the G1, S, G2, and M phases. S, G1, G2, and M are the four phases of mitosis.

Scientific Papers found: Click to Expand⟱

2230-

SK,

Shikonin induces ROS-based mitochondria-mediated apoptosis in colon cancer

in-vitro,

CRC,

HCT116

in-vivo,

NA,

TumCG↓, Bcl-2↓, ROS↑, Bcl-xL↓, MMP↓, Casp↑, selectivity↑, cycD1/CCND1↓, TumCCA↑, eff↓,

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↓,

2227-

SK,

Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species

in-vitro,

GC,

BGC-823

13.35uM

in-vitro,

GC,

SGC-7901

9.63uM

in-vitro,

Nor,

GES-1

>20 μM

selectivity↑, TumCP↓, TumCD↑, ROS↑, MMP↓, Casp↑, Cyt‑c↑, Endon↑, AIF↑, eff↓, ChemoSen↑, TumCCA↑, GSH/GSSG↓, lipid-P↑,

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↓,

5104-

SK,

Shikonin induces cell cycle arrest in human gastric cancer (AGS) by early growth response 1 (Egr1)-mediated p21 gene expression.

in-vitro,

GC,

AGS

12.5-100 ng/mL dosage of shikonin treatment on AGS cancer cell

TumCP↓, TumCCA↑, P21↑,

5102-

SK,

GEM,

Shikonin suppresses tumor growth and synergizes with gemcitabine in a pancreatic cancer xenograft model: Involvement of NF-κB signaling pathway

TumCG↓, ChemoSen↑, NF-kB↓, PCNA↓, Ki-67↓, p‑EGFR↓, ROS↑, TumCCA↑, P53↑, JNK↑, Akt↓,

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,

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,

Review,

IBD,

Review,

Stroke,

*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↝,

2008-

SK,

Cisplatin,

Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo

in-vitro,

CRC,

HCT116

in-vivo,

NA,

mice

ChemoSen↑, selectivity↑, i-ROS↑, DNAdam↑, MMP↓, TumCCA↑, eff↓, *toxicity↓,

1312-

SK,

Shikonin induces apoptosis through reactive oxygen species/extracellular signal-regulated kinase pathway in osteosarcoma cells

in-vitro,

OS,

143B

0-8uM

2.01microM

ROS↑, p‑ERK↑, Bcl-2↓, cl‑PARP↑, Apoptosis↑, TumCCA↑, Bcl-2↑, proCasp3↓,

965-

SK,

Shikonin suppresses proliferation and induces cell cycle arrest through the inhibition of hypoxia-inducible factor-1α signaling

in-vitro,

CRC,

HCT116

(0.3 to 30 uM)

shikonin did not adversely affect cell viability up to a concentration of 10 uM

in-vitro,

CRC,

SW-620

Hif1a↓, ROS↓, mTOR↓, p70S6↓, 4E-BP1↓, eIF2α↓, TumCCA↑, TumCP↓, Half-Life↝,

2198-

SK,

Shikonin suppresses proliferation of osteosarcoma cells by inducing ferroptosis through promoting Nrf2 ubiquitination and inhibiting the xCT/GPX4 regulatory axis

in-vitro,

OS,

MG63

 0.75 uM, 1.5 uM and 3 uM

1.432 uM

in-vitro,

OS,

143B

1.638 uM

TumCP↓, TumCCA↑, Ferroptosis↑, Iron↑, ROS↑, lipid-P↑, MDA↑, mtDam↑, NRF2↓, xCT↓, GPx4↓, GSH/GSSG↓, Keap1↑,

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,

(20μg/dose/day)

mice

tumCV↓, TumCCA↑, Apoptosis↑, EGFR↓, PI3K↓, Hif1a↓, PKM2↓, cycD1/CCND1↓, AntiTum↑,

Showing Research Papers: 1 to 14 of 14

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 14

Pathway results for Effect on Cancer / Diseased Cells:

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, toxicity↓, 1,
Total Targets: 19

Scientific Paper Hit Count for: TumCCA, Tumor cell cycle arrest

14 Shikonin
1 Gemcitabine (Gemzar)
1 Cisplatin

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#:322  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

Shikonin / TumCCA Cancer Research Results

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Kinase & Signal Transduction ⓘ

Transcription & Epigenetics ⓘ

Protein Folding & ER Stress ⓘ

Autophagy & Lysosomes ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Immune & Inflammatory Signaling ⓘ

Cellular Microenvironment ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Cell Death ⓘ

Transcription & Epigenetics ⓘ

Proliferation, Differentiation & Cell State ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Functional Outcomes ⓘ

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