Piperlongumine / GPx4 Cancer Research Results

PL, Piperlongumine: Click to Expand ⟱
Features:
Piperlongumine (also called Piplartine), an alkaloid from long pepper fruit
-Piperlongumine is a bioactive alkaloid derived from the long pepper (Piper longum)
– Piperlongumine has been shown to selectively increase ROS levels in cancer cells.
-NLRP3 inhibitor?
-TrxR inhibitor (major antioxidant system) to increase ROS in cancer cells
-ic50 cancer cells maybe 2-10uM, normal cells maybe exceeding 20uM.

Available from mcsformulas.com
-(Long Pepper, 500mg/Capsule)- 1 capsule 3 times daily with food
-Piperlongumine Pro Liposomal, 40 mg-take 1 capsule daily with plenty of water, after a meal

-Note half-life 30–60 minutes
BioAv poor aqueous solubility and bioavailability
Pathways:
- induce ROS production in cancer cells likely at any dose. Effect on normal cells is inconclusive.
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, Prx,
- Lowers some AntiOxidant markers/ defense in Cancer Cells: but mostly raises NRF2 (raises antiO defense), TrxR↓(*important), GSH↓ Catalase↓ HO1↓ GPx↓
- Very little indication of raising AntiOxidant defense in Normal Cells: GSH↑,
- lowers Inflammation : NF-kB↓, COX2↓, conversely p38↑, Pro-Inflammatory Cytokines : NLRP3↓, IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMP2↓, MMP9↓, VEGF↓, NF-κB↓, CXCR4↓, ERK↓
- reactivate genes thereby inhibiting cancer cell growth : HDAC↓(few reports), DNMT1↓, DNMT3A↓, EZH2↓, P53↑, HSP↓, Sp proteins↓,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, CDK2↓, CDK4↓, CDK6↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, ERK↓, EMT↓,
- small indication of inhibiting glycolysis : HIF-1α↓, cMyc↓, LDH↓, HK2↓,
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, β-catenin↓, ERK↓, JNK,
- Synergies: chemo-sensitization, RadioSensitizer, Others(review target notes), Neuroprotective, Cognitive, Hepatoprotective, CardioProtective,

- Selectivity: Cancer Cells vs Normal Cells
Rank Pathway / Target Axis Direction Primary Effect Notes / Cancer Relevance Ref
1 Transformation-linked oxidative stress dependence ↑ ROS Cancer-selective stress overload Landmark study: piperlongumine selectively kills cells with a cancer genotype by elevating ROS; antioxidant rescue blocks killing (ref)
2 GSTP1 redox buffering (glutathione S-transferase π) ↓ GSTP1 function / ↑ ROS Disables antioxidant buffering Biochemical/structural work describing GSTP1 as a piperlongumine target and linking PL exposure to increased ROS and decreased GSH (ref)
3 ER stress / UPR via PRDX4 (Peroxiredoxin 4) ↓ PRDX4 activity / ↑ ER stress Proteotoxic stress, preferential glioma killing Piperlongumine inactivates PRDX4, exacerbates ER stress, increases ROS, and preferentially kills high-grade glioma cells (ref)
4 Mitochondrial disruption + stress MAPK (JNK) ↓ ΔΨm / ↑ JNK Mitochondrial apoptosis signaling Example mechanistic paper: piperlongumine induces ROS-mediated mitochondrial disruption and activates JNK associated with apoptosis (ref)
5 DNA damage response ↑ DNA damage Checkpoint activation, death signaling Piperlongumine elevates ROS and causes DNA damage in pancreatic cancer models; antioxidant reverses DNA damage and killing (ref)
6 STAT3 signaling ↓ STAT3 activity (↓ pSTAT3 / ↓ STAT3 function) Reduced survival & stem-like growth Drug-repositioning study identifies piperlongumine as a direct STAT3 inhibitor; shows reduced STAT3 activation and mammosphere inhibition (ref)
7 NF-κB signaling ↓ NF-κB DNA binding / ↓ nuclear translocation Reduced inflammatory & anti-apoptotic transcription Piperlongumine down-regulates NF-κB DNA-binding activity and decreases nuclear translocation of p50/p65 in prostate cancer cells (ref)
8 PI3K–AKT–mTOR pathway ↓ PI3K/AKT/mTOR signaling Growth suppression; promotes apoptosis/autophagy Paper explicitly reporting piperlongumine induces apoptosis and autophagy through inhibition of PI3K/Akt/mTOR in lung cancer cells (ref)
9 p38 signaling (stress kinase) ↑ p38 signaling Stress response; autophagy involvement Mechanistic study showing piperlongumine induces autophagy by targeting p38 signaling (ref)
10 Cell cycle regulation ↑ G2/M arrest Proliferation block Demonstrates piperlongumine induces G2/M cell-cycle arrest in MCF-7 cells (cell cycle distribution shift shown) (ref)
11 EMT / migration / invasion ↓ EMT / ↓ migration & invasion Anti-metastatic phenotype Reports piperlongumine inhibits TGF-β–induced EMT and reduces migration/invasion in cancer cells (ref)
12 Ferroptosis (iron-dependent oxidative death) ↑ ferroptosis Non-apoptotic killing modality Shows piperlongumine-induced cancer cell death is inhibited by ferroptosis inhibitors and iron chelation, supporting ferroptosis involvement (ref)


GPx4, Glutathione Peroxidase 4: Click to Expand ⟱
Source:
Type:
GPX4 (Glutathione Peroxidase 4) is a selenoprotein that plays a crucial role in the regulation of ferroptosis, a form of programmed cell death characterized by the iron-dependent accumulation of lipid reactive oxygen species (ROS).
GPX4 has been found to be upregulated in several tumor types, promoting cancer cell survival and resistance to therapy. For instance, GPX4 overexpression has been observed in renal cell carcinoma, pancreatic ductal adenocarcinoma, and triple-negative breast cancer, among others. -GPX4 is known as a lipid peroxidation inhibitor protein, and its antioxidant effect is closely related to ferrous iron
Scientific Papers found: Click to Expand⟱
2958- PL,    Natural product piperlongumine inhibits proliferation of oral squamous carcinoma cells by inducing ferroptosis and inhibiting intracellular antioxidant capacity
- in-vitro, Oral, HSC3
TumCP↓, lipid-P↑, ROS↑, DNMT1↑, FTH1↓, GPx4↓, eff↓, GSH↓, Ferroptosis↑, MDA↓,

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 ⓘ

Ferroptosis↑, 1,   GPx4↓, 1,   GSH↓, 1,   lipid-P↑, 1,   MDA↓, 1,   ROS↑, 1,  

Metal & Cofactor Biology ⓘ

FTH1↓, 1,  

Cell Death ⓘ

Ferroptosis↑, 1,  

DNA Damage & Repair ⓘ

DNMT1↑, 1,  

Migration ⓘ

TumCP↓, 1,  

Drug Metabolism & Resistance ⓘ

eff↓, 1,  
Total Targets: 11

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: GPx4, Glutathione Peroxidase 4
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#:134  Target#:643  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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