Betulinic acid / PKM2 Cancer Research Results

BetA, Betulinic acid: Click to Expand ⟱
Features:
Betulinic acid "buh-TOO-li-nik acid" is a natural compound with antiretroviral, anti malarial, anti-inflammatory and anticancer properties. It is found in the bark of several plants, such as white birch, ber tree and rosemary, and has a complex mode of action against tumor cells.
-Betulinic acid is a naturally occurring pentacyclic triterpenoid
-vitro concentrations range from 1–100 µM, in vivo studies in rodents have generally used doses from 10–100 mg/kg
Precursor: Betulin, via oxidation at C-28
Lipophilicity: High (poor aqueous solubility)

Betulinic acid — Betulinic acid is a naturally occurring lupane-type pentacyclic triterpenoid with broad experimental anticancer activity, especially against melanoma, neuroectodermal, glioma, breast, colorectal, and other solid-tumor models. It is a natural-product small molecule, usually abbreviated BA or BetA, and is found in several plants, classically birch bark, with semi-synthesis commonly starting from betulin. A distinguishing feature is preferential induction of tumor-cell death through direct mitochondrial injury with relative sparing of many non-neoplastic cells in preclinical systems. Its main translational limitation is very poor aqueous solubility with correspondingly weak oral/systemic developability unless formulation or derivatization is used.

Primary mechanisms (ranked):

  1. Direct mitochondrial membrane permeabilization with intrinsic apoptosis activation
  2. Mitochondrial ROS increase with collapse of mitochondrial membrane potential and cytochrome c release
  3. ER-stress and unfolded-protein-response activation, including GRP78-linked stress signaling
  4. Suppression of NF-κB and other pro-survival transcriptional programs, including Sp-family signaling in some models
  5. Cell-cycle arrest with reduced cyclin/CDK signaling
  6. Anti-migratory and anti-invasive effects via EMT, FAK, ROCK1, MMP, and cytoskeletal remodeling pathways
  7. Secondary metabolic suppression of aerobic glycolysis and hypoxia-response signaling in susceptible models
  8. Adjunct sensitization to chemo- or radiotherapy in selected preclinical settings

Bioavailability / PK relevance: Betulinic acid is highly lipophilic and poorly water-soluble, which strongly limits oral absorption and systemic exposure. PK behavior is formulation-dependent, and much of the translational literature focuses on nanoparticles, liposomes, micelles, conjugates, or topical delivery rather than conventional oral dosing.

In-vitro vs systemic exposure relevance: Many in-vitro anticancer studies use low-to-mid micromolar concentrations, which are often difficult to reproduce reliably in vivo with unformulated parent betulinic acid. Accordingly, mechanistic findings are useful biologically, but direct concentration matching to standard oral/systemic use is often poor unless enhanced-delivery systems are used.

Clinical evidence status: Strong preclinical and formulation-development literature; very limited human oncology evidence. Cancer-facing clinical development appears to remain early-phase/topical, with orphan designation for topical metastatic melanoma but no FDA approval for that indication. Betulinic acid itself is not an established approved anticancer drug.

-half-life reports vary 3-5 hrs?. Reported half-life varies by formulation and species; several studies report multi-hour systemic persistence.
BioAv -hydrophobic molecule with relatively poor water solubility. 
Main Cancer action
-Direct mitochondrial targeting in cancer cells
-Minimal effect on normal cells

Key pathways
-Mitochondrial membrane permeabilization
-ROS-mediated apoptosis
-Caspase-independent death

Chemo relevance: Generally compatible, Not a redox buffer

Pathways:
- often induce ROS production
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓
- Lowers AntiOxidant defense in Cancer Cells(Often associated with reduced redox buffering capacity in tumor cells (e.g., GSH depletion); NRF2 direction model-dependent.): NRF2↓, SOD↓, GSH↓
- May Raise AntiOxidant defense in Normal Cells: NRF2↑, SOD↑, GSH↑, Catalase↑ Reports suggest relative sparing of normal cells and preservation of antioxidant capacity in some models
- lowers Inflammation : NF-kB↓(typ), COX2↓, p38↓ (context-dependent; often stress-activated), Pro-Inflammatory Cytokines : IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : , MMPs↓, MMP2↓, MMP9↓, TIMP2, IGF-1↓, VEGF↓, ROCK1↓, FAK↓, NF-κB↓, TGF-β↓, α-SMA↓, ERK↓
- reactivate genes thereby inhibiting cancer cell growth : P53↑, HSP↓(model-dependent), Sp proteins↓,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, CDK2↓, CDK4↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, FAK↓, ERK↓, EMT↓, TOP1↓,
- inhibits glycolysis (secondary to mitochondrial stress) ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, HK2↓, ECAR↓, GRP78↑(ER stress), GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓,
- inhibits Cancer Stem Cells in some studies : CSC↓, GLi1↓, β-catenin↓, OCT4↓,
- Others: PI3K↓(typ), AKT↓(typ), JAK↓, STAT↓, β-catenin↓, AMPK↓(AMPK is often activated during metabolic stress), ERK↓, JNK,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,
- Selectivity: Cancer Cells vs Normal Cells

Mechanistic profile

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Mitochondrial permeabilization ↑ MOMP, ↓ ΔΨm, ↑ cytochrome c release, ↑ apoptosis ↔ / milder effect P-R Core tumor-selective death trigger Best-supported central mechanism; helps explain activity in apoptosis-competent but therapy-resistant tumors.
2 Mitochondrial ROS increase ↑ ROS ↔ / possible antioxidant sparing (context-dependent) P-R Amplifies mitochondrial stress and death signaling ROS appears mechanistically relevant in many tumor models, but not every study makes it the dominant initiating event.
3 Caspase axis and caspase-independent death ↑ caspase-9, ↑ caspase-3, ↑ PARP cleavage; caspase-independent death also reported ↔ R-G Executes apoptosis after mitochondrial injury BA can still kill some tumor cells when classical caspase execution is partly blocked, indicating non-canonical death contribution.
4 ER stress / UPR / GRP78 ↑ ER stress, ↑ UPR, ↑ GRP78 stress signaling ↔ R-G Links proteostatic stress to apoptosis and metastasis suppression Especially relevant in breast and gastric cancer models; may also connect to metabolic suppression and chemosensitization.
5 NF-κB survival signaling ↓ NF-κB ↔ / ↓ inflammatory tone R-G Reduces survival, inflammatory, and resistance programs Common downstream convergence node across several tumor types.
6 Cell-cycle machinery ↓ cyclin D1, ↓ CDK2, ↓ CDK4, ↑ cell-cycle arrest ↔ G Slows proliferation Usually supportive rather than primary; often follows stress and survival-pathway disruption.
7 EMT / invasion / matrix remodeling ↓ EMT, ↓ FAK, ↓ ROCK1, ↓ MMP2, ↓ MMP9, ↓ migration, ↓ invasion ↔ G Antimetastatic effect Consistent with reduced motility and invasive phenotype in multiple solid-tumor models.
8 Glycolysis ↓ glucose uptake, ↓ lactate, ↓ ECAR, ↓ HK2, ↓ PKM2, ↓ LDHA ↔ G Secondary metabolic suppression Not the universal initiating mechanism; appears important in selected breast-cancer and GRP78-linked systems.
9 HIF-1α hypoxia axis ↓ HIF-1α, ↓ VEGF, ↓ GLUT1, ↓ PDK1 ↔ G Reduces hypoxic adaptation and angiogenic drive Relevant in hypoxic tumor biology and helps explain antiangiogenic/metabolic effects in some models.
10 NRF2 / antioxidant buffering ↓ NRF2 or ↓ redox buffering (model-dependent) ↔ / possible preservation of antioxidant tone (context-dependent) R-G May widen tumor redox vulnerability Direction is not uniform across all models; safer to treat this as contextual rather than universally core.
11 Ca²⁺ stress ↑ Ca²⁺ (context-dependent) ↔ P-R Supports organelle stress and apoptotic signaling Usually part of the broader mitochondrial/ER stress network rather than a stand-alone primary target.
12 Radiosensitization or Chemosensitization ↑ sensitivity to radiation or selected drugs Unclear G Adjunct leverage Preclinical evidence supports additive or sensitizing effects with irradiation and with some chemotherapy settings, but this is not yet clinically established.
13 Clinical Translation Constraint Poor solubility and limited systemic exposure constrain reproducibility Same formulation constraint G Delivery bottleneck Main barrier is not lack of mechanistic richness but drug-like exposure; translation currently depends heavily on formulation, derivatization, or topical/local use.

Time-Scale Flag (TSF): P / R / G

  • P: 0–30 min (primary/physical-chemical effects; rapid kinase/redox signaling)
  • R: 30 min–3 hr (acute redox and stress-response activation)
  • G: >3 hr (gene-regulatory adaptation and phenotypic 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⟱
2740- BetA,    Effects and mechanisms of fatty acid metabolism-mediated glycolysis regulated by betulinic acid-loaded nanoliposomes in colorectal cancer
- in-vitro, CRC, HCT116
TumCP↓, Glycolysis↓, HK2↓, PFK1↓, PKM2↓, ACSL1↓, CPT1A↓, FASN↓, FAO↓, GlucoseCon↓, lactateProd↓,

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:


Core Metabolism/Glycolysis ⓘ

ACSL1↓, 1,   CPT1A↓, 1,   FAO↓, 1,   FASN↓, 1,   GlucoseCon↓, 1,   Glycolysis↓, 1,   HK2↓, 1,   lactateProd↓, 1,   PFK1↓, 1,   PKM2↓, 1,  

Migration ⓘ

TumCP↓, 1,  
Total Targets: 11

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#:42  Target#:772  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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