Celastrol / PKM2 Cancer Research Results

Cela, Celastrol: Click to Expand ⟱
Features:

Celastrol — a quinone methide pentacyclic triterpenoid natural product isolated mainly from Tripterygium wilfordii and related Celastraceae plants. It is best classified as a pleiotropic redox-reactive small molecule with proteostasis-disrupting, anti-inflammatory, and anticancer activity. Standard abbreviations include Cel and CeT. In oncology, celastrol is best viewed as a preclinical multi-target stress inducer rather than a selective single-node inhibitor, with recurring emphasis on thiol-reactive proteostasis disruption, NF-κB suppression, ROS-linked mitochondrial injury, and context-dependent inhibition of STAT3 and PI3K/AKT signaling. Clinically important caveats are poor water solubility, poor oral bioavailability, rapid disposition, and a narrow therapeutic window that has driven strong interest in nanoformulations and conjugates.

Primary mechanisms (ranked):

  1. Proteostasis disruption with functional HSP90 inhibition and heat-shock response activation
  2. NF-κB pathway suppression through inhibition of pro-survival inflammatory signaling
  3. ROS elevation with mitochondrial dysfunction and intrinsic apoptosis
  4. JAK2/STAT3 axis inhibition in responsive tumor contexts
  5. Secondary down-modulation of PI3K/AKT/mTOR and related growth-survival signaling
  6. Context-dependent suppression of invasion, angiogenesis, and metastatic programs including CXCR4 and HIF-1-related outputs
  7. Chemosensitization and stress-vulnerability amplification in selected resistant tumor models

Bioavailability / PK relevance: Celastrol is practically insoluble or very poorly soluble in water, has poor oral bioavailability, and shows dose-limiting systemic toxicity; delivery systems are commonly used to improve exposure and reduce off-target injury.

In-vitro vs systemic exposure relevance: Many mechanistic and cytotoxicity studies use low-micromolar concentrations that are difficult to reproduce safely with conventional systemic dosing. Some pathway effects may still occur at lower exposures, but direct tumoricidal effects are often concentration-limited without advanced formulations.

Clinical evidence status: Strong preclinical oncology signal; early translational and formulation work; no approved cancer indication. Human clinical registration appears limited to non-oncology safety/other exploratory studies rather than established anticancer efficacy trials. *** Appears more useful used at lower doses in combined treatment approaches.

Celastrol—a bioactive compound extracted from traditional Chinese medicinal plants such as Tripterygium wilfordii (Thunder God Vine).

Pathways:
-inhibit NF-κB activation
-disrupt the function of chaperone proteins like HSP90 and HSP70, which are often overexpressed in cancer cells
-attenuate Akt phosphorylation and downstream mTOR signaling
-modulate components of the MAPK pathway, including ERK, JNK, and p38.
-increase intracellular ROS levels in cancer cells
-inhibiting STAT3

Celastrol mechanistic map in cancer

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 HSP90 proteostasis disruption ↓ client protein stability; ↑ heat-shock stress ↑ stress response (dose-dependent) P/R Destabilization of oncogenic signaling networks Mechanistically central and industry-relevant. Celastrol behaves as a thiol-reactive disruptor of chaperone-dependent proteostasis rather than a highly selective kinase inhibitor.
2 NF-κB inflammatory survival signaling ↓ ↓ inflammatory tone R/G Reduced survival, proliferation, cytokine signaling, and invasion One of the most reproducible anticancer themes; also helps explain anti-inflammatory overlap outside oncology.
3 Mitochondrial ROS increase ↑ (primary; dose-dependent) ↑ (high concentration only) P/R Oxidative stress overload and stress sensitization The quinone methide scaffold is redox-reactive. ROS often acts upstream of mitochondrial depolarization, apoptosis, and therapy sensitization.
4 Mitochondria and intrinsic apoptosis MMP ↓; Bax/Bcl-2 balance toward apoptosis; caspases ↑ ↑ injury at higher exposure R/G Apoptotic tumor cell death Usually linked to ROS and proteotoxic stress rather than an isolated primary target.
5 JAK2 STAT3 signaling ↓ (context-dependent) ↔ R/G Reduced proliferation, survival, and inflammatory transcription Supported in multiple tumor models, including myeloma and more recent metastatic-cancer work, but not necessarily dominant in every model.
6 PI3K AKT mTOR axis ↓ (secondary) ↔ / ↓ R/G Anabolic and survival suppression Often appears downstream of broader stress and chaperone disruption.
7 Invasion metastasis and angiogenesis programs CXCR4 ↓; motility ↓; VEGF signaling ↓; HIF-1α ↔ (context-dependent) ↔ G Reduced metastatic competence and tumor vascular support HIF-1-related effects are mixed across sources and models; anti-invasive and anti-angiogenic effects are better supported than a uniform HIF-1α direction.
8 NRF2 antioxidant response ↑ adaptive defense or overwhelm (context-dependent) ↑ cytoprotective stress response R/G Bidirectional redox adaptation Relevant, but not a clean core anticancer mechanism. NRF2 activation can be protective in normal tissue yet may also buffer tumor oxidative stress in some settings.
9 Chemosensitization ↑ therapy response ↔ / toxicity risk G Overcoming resistance in selected models Supported especially where NF-κB/STAT3-dependent resistance is prominent; still largely preclinical.
10 Clinical Translation Constraint Exposure limited Toxicity limited — Narrow therapeutic window Poor solubility, poor oral bioavailability, rapid metabolism/disposition, and organ-toxicity risk are major barriers to systemic oncology use.

TSF legend:
P: 0–30 min (direct redox/protein interactions)
R: 30 min–3 hr (acute stress and signaling shifts)
G: >3 hr (gene regulation and phenotype outcomes)
PKM2, Pyruvate Kinase, Muscle 2: Click to Expand ⟱
Source:
Type: enzyme
PKM2 (Pyruvate Kinase, Muscle 2) is an enzyme that plays a crucial role in glycolysis, the process by which cells convert glucose into energy. PKM2 is a key regulatory enzyme in the glycolytic pathway, and it is primarily expressed in various tissues, including muscle, brain, and cancer cells.
-C-myc is a common oncogene that enhances aerobic glycolysis in the cancer cells by transcriptionally activating GLUT1, HK2, PKM2 and LDH-A
-PKM2 has been shown to be overexpressed in many types of tumors, including breast, lung, and colon cancer. This overexpression may contribute to the development and progression of cancer by promoting glycolysis and energy production in cancer cells.
-inhibition of PKM2 may cause ATP depletion and inhibiting glycolysis.
-PK exists in four isoforms: PKM1, PKM2, PKR, and PKL
-PKM2 plays a role in the regulation of glucose metabolism in diabetes.
-PKM2 is involved in the regulation of cell proliferation, apoptosis, and autophagy.
– Pyruvate kinase catalyzes the final, rate-limiting step of glycolysis, converting phosphoenolpyruvate (PEP) to pyruvate with the production of ATP.
– The PKM2 isoform is uniquely regulated and can exist in both highly active tetrameric and less active dimeric forms.
– Cancer cells often favor the dimeric form of PKM2 to slow pyruvate production, thereby accumulating upstream glycolytic intermediates that can be diverted into anabolic pathways to support cell growth and proliferation.
– Under low oxygen conditions, cancer cells rely on altered metabolic pathways in which PKM2 is a key player. – The shift to aerobic glycolysis (Warburg effect) orchestrated in part by PKM2 helps tumor cells survive and grow in hypoxic conditions.

– Elevated expression of PKM2 is frequently observed in many cancer types, including lung, breast, colorectal, and pancreatic cancers.
– High levels of PKM2 are often correlated with enhanced tumor aggressiveness, poor differentiation, and advanced clinical stage.

PKM2 in carcinogenesis and oncotherapy

Inhibitors of PKM2:
-Shikonin, Resveratrol, Baicalein, EGCG, Apigenin, Curcumin, Ursolic Acid, Citrate (best known as an allosteric inhibitor of phosphofructokinase-1 (PFK-1), a key rate-limiting enzyme in glycolysis) potential to directly inhibit or modulate PKM2 is less well established

Full List of PKM2 inhibitors from Database
-key connected observations: Glycolysis↓, lactateProd↓, ROS↑ in cancer cell, while some result for opposite effect on normal cells.
Tumor pyruvate kinase M2 modulators

Flavonoids effect on PKM2
Compounds name IC50/AC50uM Effect
Flavonols
1. Fisetin 0.90uM Inhibition
2. Rutin 7.80uM Inhibition
3. Galangin 8.27uM Inhibition
4. Quercetin 9.24uM Inhibition
5. Kaempferol 9.88uM Inhibition
6. Morin hydrate 37.20uM Inhibition
7. Myricetin 0.51uM Activation
8. Quercetin 3-b- D-glucoside 1.34uM Activation
9. Quercetin 3-D -galactoside 27-107uM Ineffective
Flavanons
10. Neoeriocitrin 0.65uM Inhibition
11. Neohesperidin 14.20uM Inhibition
12. Naringin 16.60uM Inhibition
13. Hesperidin 17.30uM Inhibition
14. Hesperitin 29.10uM Inhibition
15. Naringenin 70.80uM Activation
Flavanonols
16. (-)-Catechin gallateuM 0.85 Inhibition
17. (±)-Taxifolin 1.16uM Inhibition
18. (-)-Epicatechin 1.33uM Inhibition
19. (+)-Gallocatechin 4-16uM Ineffective
Phenolic acids
20. Ferulic 11.4uM Inhibition
21. Syringic and 13.8uM Inhibition
22. Caffeic acid 36.3uM Inhibition
23. 3,4-Dihydroxybenzoic acid 78.7uM Inhibition
24. Gallic acid 332.6uM Inhibition
25. Shikimic acid 990uM Inhibition
26. p-Coumaric acid 22.2uM Activation
27. Sinapinic acids 26.2uM Activation
28. Vanillic 607.9uM Activation


Scientific Papers found: Click to Expand⟱
2392- Cela,    The role of natural products targeting macrophage polarization in sepsis-induced lung injury
- Review, Sepsis, NA
TNF-α↓, IL1β↓, IL6↓, Warburg↓, PKM2↓, NRF2↑, HO-1↑, NF-kB↓, iNOS↓, M1↓,
2393- Cela,    Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect
- in-vivo, Sepsis, NA - in-vitro, Nor, RAW264.7
OS↑, PKM2↓, Glycolysis↓, Warburg↓, Inflam↓, HMGB1↓, ALAT↓, AST↓, TNF-α↓, IL1β↓, IL6↓,

Showing Research Papers: 1 to 2 of 2

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 2

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

HO-1↑, 1,   NRF2↑, 1,  

Core Metabolism/Glycolysis ⓘ

ALAT↓, 1,   Glycolysis↓, 1,   PKM2↓, 2,   Warburg↓, 2,  

Cell Death ⓘ

iNOS↓, 1,  

Immune & Inflammatory Signaling ⓘ

HMGB1↓, 1,   IL1β↓, 2,   IL6↓, 2,   Inflam↓, 1,   M1↓, 1,   NF-kB↓, 1,   TNF-α↓, 2,  

Clinical Biomarkers ⓘ

ALAT↓, 1,   AST↓, 1,   IL6↓, 2,  

Functional Outcomes ⓘ

OS↑, 1,  
Total Targets: 18

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: PKM2, Pyruvate Kinase, Muscle 2
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#:317  Target#:772  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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