Database Query Results : Piperlongumine, , MMP2

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)


MMP2, metalloproteinase-2: Click to Expand ⟱
Source:
Type:
Matrix metalloproteinase-2 (MMP-2) is an enzyme that plays a significant role in the degradation of extracellular matrix components, which is crucial for various physiological processes, including tissue remodeling, wound healing, and angiogenesis.
Elevated levels of MMP-2 have been associated with poor prognosis in various cancers, including breast, lung, and colorectal cancers.
MMP2 and MMP9: two enzymes are critical to tumor invasion.
Scientific Papers found: Click to Expand⟱
2973- PL,    The Natural Alkaloid Piperlongumine Inhibits Metastatic Activity and Epithelial-to-Mesenchymal Transition of Triple-Negative Mammary Carcinoma Cells
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, 4T1
MMP2↓, Piperlongumine-treated MDA-MB-231 cells showed reduced motility/invasiveness, decreased MMP2 and MMP9 expression,
MMP9↓,
IL6↓, increased miR-200c expression, reduced IL-6 synthesis, decreased expression of ZEB1 and Slug, increased E-cadherin expression, and epithelial-like morphology.
E-cadherin↑,
ROS↑, ROS accumulated in piperlongumine-treated cells,
EMT↓, Piperlongumine Suppresses EMT
Zeb1↓, EMT-promoting ZEB1 and Slug transcription factors was significantly downregulated
Slug↓,
TumMeta↓, sub-cytotoxic dose of piperlongumine prevented metastasis in a mouse model of TNBC
selectivity↑, capacity to induce apoptosis in cancer cells while sparing normal cells
MMP2↓, Low dose piperlongumine also suppressed the expression of MMP2 and MMP9,
GSH↓, The resulting depletion of ROS-scavenging GSH would be expected to cause oxidative stress due to the accumulation of intracellular ROS


* 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 ⓘ

GSH↓, 1,   ROS↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

EMT↓, 1,  

Migration ⓘ

E-cadherin↑, 1,   MMP2↓, 2,   MMP9↓, 1,   Slug↓, 1,   TumMeta↓, 1,   Zeb1↓, 1,  

Immune & Inflammatory Signaling ⓘ

IL6↓, 1,  

Drug Metabolism & Resistance ⓘ

selectivity↑, 1,  

Clinical Biomarkers ⓘ

IL6↓, 1,  
Total Targets: 12

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: MMP2, metalloproteinase-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#:134  Target#:201  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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