Germacranolide sesquiterpene lactone / cycD1/CCND1 Cancer Research Results

GSL, Germacranolide sesquiterpene lactone: Click to Expand ⟱
Features:
A germacranolide sesquiterpene lactone (GSL) was isolated from Siegesbeckia glabrescens

Germacranolide — Germacranolides are a structural subclass of plant-derived sesquiterpene lactones built on a ten-membered germacrane ring fused to a lactone moiety.

Primary mechanisms (ranked):

  1. Inhibition of Hedgehog effector signaling through suppression of GLI-mediated transcription, including reduced GLI1 expression.
  2. Suppression of cyclin D1 downstream of GLI, producing reduced proliferation of Hedgehog-dependent pancreatic cancer cells.
  3. Inhibition of inflammatory mediator production, including nitric oxide and prostaglandin E2, with reduced inducible nitric oxide synthase and cyclooxygenase-2 expression in activated macrophages.
  4. Electrophilic modification of protein thiols through the α-methylene-γ-lactone pharmacophore is a plausible class-level mechanism for many germacranolides, but direct target engagement has not been established for this specific S. glabrescens GSL.

Bioavailability / PK relevance: No compound-specific absorption, distribution, metabolism, excretion, plasma-exposure, or oral-bioavailability data were identified for the S. glabrescens GSL. Sesquiterpene lactones commonly have poor aqueous solubility, chemical reactivity, rapid metabolism, and nonspecific thiol binding that may limit systemic exposure and therapeutic index. Pharmacokinetic findings from geraniol, germacrone, costunolide, or other germacranolides should not be assigned to this compound.

In-vitro vs systemic exposure relevance: The anticancer experiments used approximately 1–20 µM GSL for transcriptional assays and up to 20 µM for protein analyses; reported proliferation IC50 values were approximately 5.1 µM in AsPC-1 cells and higher in nonmalignant C3H10T1/2 cells. Whether these concentrations are achievable or sustainable in humans is unknown because no human or animal systemic-exposure data were reported. The evidence is therefore concentration-driven and restricted principally to cell culture.

Clinical evidence status: Preclinical only. Evidence for the specific S. glabrescens GSL consists primarily of biochemical and cell-culture studies in pancreatic cancer cells, mesenchymal reporter cells, and activated macrophages. No clinical trials, approved indications, validated dosing regimen, or human anticancer efficacy data were identified. Other germacranolides have broader preclinical anticancer literature, but that evidence cannot be generalized directly to this compound.

Mechanistic Profile

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Hedgehog GLI transcription ↓ GLI transcriptional activity
↓ GLI1		 ↓ Shh-induced differentiation signaling in C3H10T1/2 cells R–G Suppresses the terminal transcriptional output of Hedgehog signaling Central demonstrated mechanism. Activity was observed in GLI reporter systems and PANC-1 and AsPC-1 pancreatic cancer cells. The precise molecular binding target upstream of GLI remains unidentified.
2 Cyclin D1 cell-cycle signaling ↓ cyclin D1
↓ proliferation		 ↔ or less sensitive (model-dependent) G Restricts proliferative cell-cycle progression Cyclin D1 reduction is consistent with inhibition of GLI-dependent transcription. Formal phase-specific arrest was not comprehensively characterized.
3 Pancreatic cancer cell viability ↓ PANC-1 proliferation
↓ AsPC-1 proliferation		 ↓ at higher concentrations G Concentration-dependent antiproliferative activity AsPC-1 cells showed an IC50 near 5 µM, whereas C3H10T1/2 cells were less sensitive. Selectivity remains preliminary and was not established in vivo.
4 Inflammatory nitric oxide signaling Not adequately established ↓ nitric oxide
↓ inducible nitric oxide synthase (context-dependent)		 G Reduces macrophage inflammatory mediator production Demonstrated in LPS-activated RAW264.7 macrophages. This is an anti-inflammatory finding and should not automatically be interpreted as an anticancer mechanism.
5 Prostaglandin E2 and cyclooxygenase-2 Not demonstrated for the specific compound ↓ prostaglandin E2
↓ cyclooxygenase-2 (context-dependent)		 G Suppresses inflammatory prostaglandin synthesis The Nestronics COX-2 entry is supportable through the macrophage study, but not through the listed rosmarinic acid and ginsenoside Rg1 paper.
6 PI3K AKT signaling ↔ phosphorylated AKT and total AKT Not established R–G No detected modulation under the tested conditions Supports a GLI-directed effect that was independent of measurable AKT suppression in PANC-1 cells.
7 Electrophilic thiol reactivity Potential covalent protein modulation (context-dependent) Potential off-target protein binding and sensitization P–R Class-level Michael-acceptor activity The α-methylene-γ-lactone group can react with cysteine thiols. This may contribute to biological activity but also creates selectivity and toxicity constraints. Direct protein targets have not been confirmed for this GSL.
8 Clinical Translation Constraint In-vitro activity only Human safety unknown G Uncertain systemic feasibility No compound-specific PK, formulation, animal efficacy, clinical trial, or therapeutic dose data. Poor solubility, reactive electrophilicity, and possible sesquiterpene-lactone hypersensitivity are relevant class concerns.

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⟱
30- GSL,    A sesquiterpene lactone from Siegesbeckia glabrescens suppresses Hedgehog/Gli-mediated transcription in pancreatic cancer cells
- in-vitro, PC, PANC1 - in-vitro, PC, AsPC-1
HH↓, Gli1↓, Shh↓, cycD1/CCND1↓, TumCP↓,

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:


Cell Cycle & Senescence(tgid=11) ⓘ

cycD1/CCND1↓, 1,  

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

Gli1↓, 1,   HH↓, 1,   Shh↓, 1,  

Migration(tgid=13) ⓘ

TumCP↓, 1,  
Total Targets: 5

Pathway results for Effect on Normal Cells:


Total Targets: 0

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

 

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