lambertianic acid / cycD1/CCND1 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
cycD1/CCND1, cyclin D1 pathway: Click to Expand ⟱
Source:
Type:
Also called CCND1 Gatekeeper of Cell-Cycle Commitment
The main function of cyclin D1 is to maintain cell cycle and to promote cell proliferation. Cyclin D1 is a key regulatory protein involved in the cell cycle, particularly in the transition from the G1 phase to the S phase. It is part of the cyclin-dependent kinase (CDK) complex, where it binds to CDK4 or CDK6 to promote cell cycle progression.
Cyclin D1 is crucial for the regulation of the cell cycle. Overexpression or dysregulation of cyclin D1 can lead to uncontrolled cell proliferation, a hallmark of cancer.
Cyclin D1 is often found to be overexpressed in various cancers.
Cyclin D1 can interact with tumor suppressor proteins, such as retinoblastoma (Rb). When cyclin D1 is overexpressed, it can lead to the phosphorylation and inactivation of Rb, releasing E2F transcription factors that promote the expression of genes required for DNA synthesis and cell cycle progression.
Cyclin D1 is influenced by various signaling pathways, including the PI3K/Akt and MAPK pathways, which are often activated in cancer.
In some cancers, high levels of cyclin D1 expression have been associated with poor prognosis, making it a potential biomarker for cancer progression and treatment response.
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↓,
8148- lamb,    Anti-Cancer Effect of Lambertianic Acid by Inhibiting the AR in LNCaP Cells
- in-vitro, Pca, LNCaP
*antiAll↑, *Bacteria↓, AR↓, PSA↓, TumCCA↑, CDK4↓, CDK6↓, cycD1/CCND1↓, P53↑, P21↑, p27/CDKN1B↓, Apoptosis↑, cl‑Casp9↑, cl‑Casp3↑, cl‑PARP↑, BAX↑, Bcl-2↓, Dose↝,
8156- lamb,    A review on chemistry, source and therapeutic potential of lambertianic acid
- Review, Var, NA
*Obesity↓, *AntiCan↑, *AMPK↑, *β-HEX↓, NA↑, TumCCA↑, AMPK↑, ACC↑, p‑Akt↓, FOXM1↓, CycB/CCNB1↓, XIAP↓, Bcl-2↓, p‑STAT3↓, p‑NF-kB↓, Bcl-xL↓, survivin↓, VEGF↓, COX2/PTGS2↓, cMyc↓, IL6↓, TNF-α↓, ROS↑, STK11/LKB1↑, cl‑Casp3↑, cl‑PARP↑, eff↑, AR↓, TumCP↓, p‑P53↓, P21↓, p27/CDKN1B↓, cycD1/CCND1↓, CDK4↓, PSA↓, STAT3↓, ac‑p65↓, *antiAll↑,

Showing Research Papers: 1 to 3 of 3

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 3

Pathway results for Effect on Cancer / Diseased Cells:


NA, unassigned(tgid=0) ⓘ

NA↑, 1,  

Redox & Oxidative Stress(tgid=1) ⓘ

ROS↑, 2,  

Mitochondria & Bioenergetics(tgid=3) ⓘ

XIAP↓, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

ACC↑, 1,   AMPK↑, 1,   cMyc↓, 2,   Glycolysis↓, 1,   HK2↓, 1,   lactateProd↓, 1,   LDHA↓, 1,   PKM2↓, 1,   STK11/LKB1↑, 1,   Warburg↓, 1,  

Cell Death(tgid=5) ⓘ

p‑Akt↓, 1,   Apoptosis↑, 1,   BAX↑, 1,   Bcl-2↓, 2,   Bcl-xL↓, 1,   cl‑Casp3↑, 2,   proCasp3↓, 1,   cl‑Casp9↑, 1,   p27/CDKN1B↓, 2,   survivin↓, 1,  

DNA Damage & Repair(tgid=10) ⓘ

P53↑, 1,   p‑P53↓, 1,   cl‑PARP↑, 2,   proPARP↓, 1,  

Cell Cycle & Senescence(tgid=11) ⓘ

CDK4↓, 2,   CycB/CCNB1↓, 1,   cycD1/CCND1↓, 3,   P21↓, 1,   P21↑, 1,   TumCCA↑, 2,  

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

FOXM1↓, 1,   p‑GSK‐3β↓, 1,   STAT3↓, 1,   p‑STAT3↓, 2,  

Migration(tgid=13) ⓘ

TumCP↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature(tgid=14) ⓘ

VEGF↓, 1,  

Immune & Inflammatory Signaling(tgid=16) ⓘ

COX2/PTGS2↓, 1,   IL6↓, 1,   p‑NF-kB↓, 1,   ac‑p65↓, 1,   PSA↓, 2,   TNF-α↓, 1,  

Hormonal & Nuclear Receptors(tgid=20) ⓘ

AR↓, 2,   CDK6↓, 1,  

Drug Metabolism & Resistance(tgid=21) ⓘ

Dose↝, 1,   eff↓, 1,   eff↑, 1,  

Clinical Biomarkers(tgid=22) ⓘ

AR↓, 2,   FOXM1↓, 1,   IL6↓, 1,   PSA↓, 2,  
Total Targets: 55

Pathway results for Effect on Normal Cells:


NA, unassigned(tgid=0) ⓘ

antiAll↑, 2,   β-HEX↓, 1,  

Core Metabolism/Glycolysis(tgid=4) ⓘ

AMPK↑, 1,  

Functional Outcomes(tgid=23) ⓘ

AntiCan↑, 1,   Obesity↓, 1,  

Infection & Microbiome(tgid=24) ⓘ

Bacteria↓, 1,  
Total Targets: 6

Scientific Paper Hit Count for: cycD1/CCND1, cyclin D1 pathway
3 lambertianic acid
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#:73  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

 

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