lambertianic acid / PKM2 Cancer Research Results

lamb, lambertianic acid: Click to Expand ⟱
Features:

Lambertianic acid — a naturally occurring labdane-type diterpenoid carboxylic acid found in several conifer species, particularly Pinus koraiensis, Pinus lambertiana, and Platycladus orientalis. It is an experimental natural-product small molecule rather than an approved drug. The abbreviation LA is commonly used in the scientific literature, although the Nestronics product abbreviation is lamb. Lambertianic acid has reported anticancer, anti-inflammatory, anti-allergic, metabolic, and muscle-protective activities, but its therapeutic evidence remains predominantly cellular and preclinical. Its anticancer activity appears strongly context-dependent and involves coordinated effects on oxidative stress, AMPK signaling, cancer metabolism, STAT3/NF-κB survival signaling, androgen receptor signaling, and apoptosis.

Primary mechanisms (ranked):

  1. ↑ ROS with ROS-dependent activation of LKB1/AMPK/ACC signaling, producing metabolic stress and apoptosis in susceptible cancer cells.
  2. ↓ PKM2/HK2/LDHA-driven glycolysis and ↓ PKM2/β-catenin signaling, producing an anti-Warburg metabolic effect.
  3. ↓ STAT3 and NF-κB signaling, including ↓ STAT3 phosphorylation, ↓ RelA/p65 activation/acetylation, and suppression of downstream survival and inflammatory proteins.
  4. ↑ intrinsic and extrinsic apoptosis through caspase activation, PARP cleavage, ↓ BCL-2/BCL-xL/XIAP/survivin, and context-dependent ↑ DR4/TRAIL sensitivity.
  5. ↑ AMPK with ↓ AKT/mTOR and ↓ FOXM1 signaling, contributing to growth arrest and apoptosis.
  6. ↓ androgen receptor signaling in androgen-responsive prostate cancer, with ↓ AR nuclear signaling and ↓ PSA.
  7. Cell-cycle inhibition through ↓ cyclin D1/CDK4/CDK6 or ↓ cyclin B1 and context-dependent ↑ p53/p21/p27.

Bioavailability / PK relevance: Human pharmacokinetic parameters, oral bioavailability, plasma half-life, distribution, metabolism, and clinically achievable concentrations have not been adequately established. Lambertianic acid is a lipophilic diterpenoid and should therefore not be assumed to achieve the micromolar exposures used in cell-culture studies after ordinary dietary or oral exposure. No validated therapeutic dosing regimen exists.

In-vitro vs systemic exposure relevance: Most anticancer experiments use approximately 10–200 µM lambertianic acid, depending on the model. Some signaling effects occur around 15–30 µM, whereas androgen-receptor prostate-cancer experiments used substantially higher concentrations, including approximately 100–200 µM. There is currently insufficient human PK evidence to demonstrate that these concentrations are systemically achievable. Normal-cell selectivity is also incompletely characterized; recent C2C12 studies found little cytotoxicity at 12.5–25 µM but measurable loss of viability at 50–100 µM.

Clinical evidence status: Preclinical. Evidence consists primarily of cultured cancer cells with limited animal-supporting evidence from non-cancer metabolic studies. No established randomized clinical trial evidence, approved oncologic indication, validated human anticancer dose, or regulatory approval for lambertianic acid as a therapeutic agent was identified.

Lambertianic Acid Mechanisms

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 ROS-LKB1-AMPK-ACC metabolic stress ROS ↑; LKB1 ↑; AMPK ↑; ACC phosphorylation ↑ Not established G Apoptosis and metabolic stress ↑ ROS scavenging with NAC substantially reverses several anticancer effects, supporting ROS as a mechanistically important upstream event rather than merely a secondary marker.
2 Glycolysis and PKM2-beta-catenin axis PKM2 ↓; p-PKM2 ↓; HK2 ↓; LDHA ↓; lactate production ↓; beta-catenin ↓; glycolysis ↓ Not established G Warburg metabolism ↓; apoptosis ↑ Particularly demonstrated in DU145 and PC3 prostate cancer cells. ROS contributes upstream to suppression of PKM2 and associated metabolic signaling.
3 STAT3-NF-kB-p300-RelA survival signaling p-STAT3 ↓; NF-kB activation ↓; p300 ↓; RelA acetylation ↓; nuclear translocation ↓ Not established G Survival and inflammatory signaling ↓ Associated with ↓ XIAP, survivin, BCL-2, BCL-xL, VEGF, COX-2, c-Myc, IL-6 and TNF-alpha. miR-134 ↑ appears to participate in this pathway.
4 Intrinsic apoptosis Caspase-3 ↑; caspase-9 ↑; PARP cleavage ↑; BAX ↑; BCL-2 ↓ Not adequately established G Apoptosis ↑ Observed across prostate, hepatocellular, breast and lung cancer models. Apoptotic response is frequently downstream of AMPK activation and suppression of survival signaling.
5 AMPK-AKT-mTOR-FOXM1 axis AMPK ↑; AKT ↓; mTOR ↓; FOXM1 ↓; cyclin B1 ↓ AMPK modulation reported in non-cancer metabolic models G Proliferation ↓; apoptosis ↑ AMPK inhibition reverses several lambertianic-acid effects, supporting a functional rather than merely correlative role for AMPK.
6 Androgen receptor signaling AR ↓; AR nuclear translocation ↓; PSA ↓ Not established G Androgen-dependent proliferation ↓ Best demonstrated in LNCaP prostate cancer cells. Relatively high concentrations were required compared with several later mechanistic studies.
7 Cell-cycle regulation Cyclin D1 ↓; CDK4 ↓; CDK6 ↓; p53 ↑; p21 ↑; p27 ↑; cyclin B1 ↓ Not established G G1 or G2/M arrest ↑ (model-dependent) Cell-cycle phenotype varies by cancer model. LNCaP cells predominantly demonstrate G1 arrest, whereas breast-cancer studies report G2/M-associated effects.
8 TRAIL death-receptor sensitization DR4 ↑; caspase-8 ↑; Bid activation ↑; XIAP ↓; FLIP ↓; NF-kB ↓ Not established G TRAIL-induced apoptosis ↑ Lambertianic acid sensitized A549 and H1299 non-small-cell lung cancer cells to TRAIL. This is a combination-dependent chemosensitization-like mechanism rather than evidence of clinical combination efficacy.
9 Angiogenic and inflammatory survival factors VEGF ↓; COX-2 ↓; IL-6 ↓; TNF-alpha ↓ COX-2, IL-6, PGD2 and LTC4 ↓ in activated mast-cell models G Inflammatory and pro-survival signaling ↓ These effects overlap substantially with suppression of STAT3 and NF-kB and are therefore best considered downstream or secondary mechanisms.
10 Clinical Translation Constraint Effective concentrations commonly in micromolar range Normal-cell therapeutic window incompletely defined G Clinical applicability uncertain Human PK, oral bioavailability, dose-limiting toxicity, target exposure, long-term safety and anticancer efficacy have not been established. Current evidence does not justify assuming that experimental concentrations are achievable in humans.

P: 0–30 min    R: 30 min–3 hr    G: >3 hr
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⟱
2351- lamb,    Anti-Warburg effect via generation of ROS and inhibition of PKM2/β-catenin mediates apoptosis of lambertianic acid in prostate cancer cells
- in-vitro, Pca, DU145 - in-vitro, Pca, PC3
proCasp3↓, proPARP↓, LDHA↓, Glycolysis↓, HK2↓, PKM2↓, lactateProd↓, p‑STAT3↓, cycD1/CCND1↓, cMyc↓, β-catenin/ZEB1↓, p‑GSK‐3β↓, ROS↑, eff↓, Warburg↓,

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(tgid=1) ⓘ

ROS↑, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

cMyc↓, 1,   Glycolysis↓, 1,   HK2↓, 1,   lactateProd↓, 1,   LDHA↓, 1,   PKM2↓, 1,   Warburg↓, 1,  

Cell Death(tgid=5) ⓘ

proCasp3↓, 1,  

DNA Damage & Repair(tgid=10) ⓘ

proPARP↓, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

cycD1/CCND1↓, 1,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

p‑GSK‐3β↓, 1,   p‑STAT3↓, 1,  

Migration(tgid=13) ⓘ

β-catenin/ZEB1↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

eff↓, 1,  
Total Targets: 15

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

 

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