Database Query Results : Piperlongumine, , TumCMig

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)


TumCMig, Tumor cell migration: Click to Expand ⟱
Source:
Type:
Tumor cell migration is a critical process in cancer progression and metastasis, which is the spread of cancer cells from the primary tumor to distant sites in the body.
Scientific Papers found: Click to Expand⟱
2952- PL,    Piperlongumine suppresses bladder cancer invasion via inhibiting epithelial mesenchymal transition and F-actin reorganization
- in-vitro, Bladder, T24/HTB-9 - in-vivo, Bladder, NA
TumCP↓, PL significantly suppressed bladder cancer cell proliferation, the transition of G2/M phase to next phase, migration/invasion in vitro and bladder cancer growth/development in vivo
TumCCA↑,
TumCMig↓,
TumCI↓,
ROS↑, PL markedly elevated reactive oxygen species (ROS)
Slug↓, PL inhibited epithelial mesenchymal transition with profoundly decreased level of Slug, β-catenin, ZEB1 and N-Cadherin.
β-catenin/ZEB1↓,
Zeb1↓,
N-cadherin↓,
F-actin↓, decreased F-actin intensity in bladder cancer cells
GSH↓, Consistently, intracellular glutathione (GSH) levels were significantly reduced in T24 cells at 3 h of PL treatment
EMT↓, PL inhibited epithelial mesenchymal transition
CLDN1↓, The decline of Claudin-1 and ZO-1 upon PL treatment
ZO-1↓,

2957- PL,    Piperlongumine Induces Cell Cycle Arrest via Reactive Oxygen Species Accumulation and IKKβ Suppression in Human Breast Cancer Cells
- in-vitro, BC, MCF-7
TumCP↓, We found that PL decreased MCF-7 cell proliferation and migration.
TumCMig↓,
TumCCA↑, PL induced G2/M phase cell cycle arrest.
ROS↑, PL induced intracellular reactive oxygen species (hydrogen peroxide) accumulation and glutathione depletion
H2O2↑,
GSH↓,
IKKα↓, PL-mediated inhibition of IKKβ expression decreased nuclear translocation of NF-κB p65.
NF-kB↓,
P21↑, PL significantly increased p21 mRNA levels.
eff↓, PL significantly decreased cellular GSH levels, while in cells pre-treated with NAC, the GSH levels were similar to those observed in control cells

2961- PL,    Piperlongumine inhibits esophageal squamous cell carcinoma in vitro and in vivo by triggering NRF2/ROS/TXNIP/NLRP3-dependent pyroptosis
- in-vitro, ESCC, KYSE-30
Pyro↑, PL significantly suppressed malignant behavior by promoting pyroptosis of ESCC cells by inhibiting proliferation, migration, invasion, and colony formation of KYSE-30 cells
TumCP↓,
TumCMig↓,
TumCI↓,
ASC↑, up-regulating expressions of ASC, Cleaved-caspase-1, NLRP3, and GSDMD, while inducing the generation of ROS.
cl‑Casp1↑,
NLRP3↑,
GSDMD↑,
ROS↑,
NRF2↓, PL inhibited the malignant behavior of ESCC cells in vitro and tumorigenesis of ESCC in vivo by inhibiting NRF2 and promoting ROS-TXNIP-NLRP3-mediated pyroptosis.
TXNIP↑,

2950- PL,    Overview of piperlongumine analogues and their therapeutic potential
- Review, Var, NA
AntiAg↑, PL has been shown to exert in vitro antiplatelet aggregation effect induced by agonists such as collagen, adenosine 50-diphosphate (ADP), arachidonic acid (AA) and thrombin.
neuroP↑, Neuroprotective activity of PL and its derivatives
Inflam↓, Anti-inflammatory activity of PL and its derivatives
NO↓, production of NO and PGE2 was significantly inhibited after the treatment of PL.
PGE2↓,
MMP3↓, PL also significantly suppressed the production of MMP-3 and MMP-13
MMP13↓,
TumCMig↓, PL inhibited the proliferation, induced the apoptosis and reduced the migration and invasion of RA FLS by activating the p38, JNK, NF-kB and STAT3 pathways
TumCI↓,
p38↑,
JNK↑,
NF-kB↑,
ROS↑, PL has been reported to selectively induce apoptotic by ROS accumulation in cancer cells via different molecular mechanisms.
FOXM1↓, PL inhibited proteasome including suppression of FOXM1
TrxR1↓, induction of ROS by directly inhibiting thioredoxin reductase 1 (TrxR1) activity
GSH↓, Wang et al. demonstrated that PL could inhibit both glutathione and thioredoxin and thus induce ROS elevation,
Trx↓,
cMyc↓, downregulation of c-Myc and LMP1 and the Caspase-3-dependent apoptosis of Burkitt lymphoma cells in vitro.
Casp3↑,
Bcl-2↓, PL could downregulate Bcl-2 and Mcl-1 and decrease the expression of STAT-3
Mcl-1↓,
STAT3↓, Bharadwaj et al. identified PL as a direct STAT3 inhibitor
AR↓, Golovine et al. demonstrated for the first time that PL rapidly reduced the androgen receptor protein level of prostate cancer cells
DNAdam↑, inducing DNA damage,

1939- PL,    Piperlongumine selectively kills hepatocellular carcinoma cells and preferentially inhibits their invasion via ROS-ER-MAPKs-CHOP
- in-vitro, HCC, HepG2 - in-vitro, HCC, HUH7 - in-vivo, NA, NA
TumCMig↓, PL specifically suppressed HCC cell migration/invasion via endoplasmic reticulum (ER)-MAPKs-CHOP signaling pathway
TumCI↓,
ER Stress↑, Piperlongumine induces ER stress-responses which preferentially suppresses HCC cell migration/invasion
selectivity↑, PL selectively killed HCC cells but not normal hepatocytes with an IC50 of 10-20 μM while PL at much lower concentrations only suppressed HCC cell migration/invasion
tumCV↓,
ROS↑, Piperlongumine induces ROS accumulation to exert its anti-cancer effects on HCC cells
GSH↓, Consistently, intracellular glutathione (GSH) levels were significantly reduced in HepG2 or Huh7 cells at 1 h of PL treatment
eff↓, Pre-treatment of NAC or GSH completely reversed PL-induced cell death in Huh7 cells (Fig. 3E) and HepG2 cells
Ca+2↑, concentration of cytoplasmic free Ca2+ was prominently increased at 3 h of PL treatment in a dose-dependent manner (0-20 μM)
MAPK↑, Piperlongumine activates MAPKs signaling pathways which preferentially suppress HCC migration
CHOP↑, These evidences demonstrated that PL activated ER-MAPKs-CHOP axis signaling pathways via ROS-dependent mechanisms.
Dose↝, Notably, PL at a much lower concentration (1.5 mg/kg) showed a comparable anticancer effect in HCC-bearing mice and increasing PL concentration did not significantly enhance its anticancer effects

2945- PL,    Piperlongumine induces ROS mediated cell death and synergizes paclitaxel in human intestinal cancer cells
- in-vitro, CRC, HCT116
ROS↑, Piperlongumine (PL) kills intestinal cancer cells by elevating ROS levels.
SMAD4↑, PL significantly up-regulates SMAD4 expression, leading to apoptosis in cancer cells.
ChemoSen↑, PL with Paclitaxel can be a better option for chemotherapy.
P53↑, Remarkably, P53, P21, BAX, and SMAD4 were significantly upregulated after PL treatment whereas; BCL2 and SURVIVIN were down-regulated.
P21↑,
BAX↑,
Bcl-2↓,
survivin↓,
TumCMig↓, Piperlongumine suppresses migration of cancer cell


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 6

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

GSH↓, 4,   H2O2↑, 1,   NRF2↓, 1,   ROS↑, 6,   Trx↓, 1,   TrxR1↓, 1,  

Core Metabolism/Glycolysis ⓘ

cMyc↓, 1,  

Cell Death ⓘ

BAX↑, 1,   Bcl-2↓, 2,   cl‑Casp1↑, 1,   Casp3↑, 1,   GSDMD↑, 1,   JNK↑, 1,   MAPK↑, 1,   Mcl-1↓, 1,   p38↑, 1,   Pyro↑, 1,   survivin↓, 1,  

Transcription & Epigenetics ⓘ

tumCV↓, 1,  

Protein Folding & ER Stress ⓘ

CHOP↑, 1,   ER Stress↑, 1,  

DNA Damage & Repair ⓘ

DNAdam↑, 1,   P53↑, 1,  

Cell Cycle & Senescence ⓘ

P21↑, 2,   TumCCA↑, 2,  

Proliferation, Differentiation & Cell State ⓘ

EMT↓, 1,   FOXM1↓, 1,   STAT3↓, 1,  

Migration ⓘ

AntiAg↑, 1,   Ca+2↑, 1,   CLDN1↓, 1,   F-actin↓, 1,   MMP13↓, 1,   MMP3↓, 1,   N-cadherin↓, 1,   Slug↓, 1,   SMAD4↑, 1,   TumCI↓, 4,   TumCMig↓, 6,   TumCP↓, 3,   TXNIP↑, 1,   Zeb1↓, 1,   ZO-1↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature ⓘ

NO↓, 1,  

Immune & Inflammatory Signaling ⓘ

ASC↑, 1,   IKKα↓, 1,   Inflam↓, 1,   NF-kB↓, 1,   NF-kB↑, 1,   PGE2↓, 1,  

Protein Aggregation ⓘ

NLRP3↑, 1,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 1,  

Drug Metabolism & Resistance ⓘ

ChemoSen↑, 1,   Dose↝, 1,   eff↓, 2,   selectivity↑, 1,  

Clinical Biomarkers ⓘ

AR↓, 1,   FOXM1↓, 1,  

Functional Outcomes ⓘ

neuroP↑, 1,  
Total Targets: 60

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: TumCMig, Tumor cell migration
6 Piperlongumine
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#:326  State#:%  Dir#:%
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