Piperlongumine / Casp3 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)


Casp3, CPP32, Cysteinyl aspartate specific proteinase-3: Click to Expand ⟱
Source:
Type:
Also known as CP32.
Cysteinyl aspartate specific proteinase-3 (Caspase-3) is a common key protein in the apoptosis and pyroptosis pathways, and when activated, the expression level of tumor suppressor gene Gasdermin E (GSDME) determines the mechanism of tumor cell death.
As a key protein of apoptosis, caspase-3 can also cleave GSDME and induce pyroptosis. Loss of caspase activity is an important cause of tumor progression.
Many anticancer strategies rely on the promotion of apoptosis in cancer cells as a means to shrink tumors. Crucial for apoptotic function are executioner caspases, most notably caspase-3, that proteolyze a variety of proteins, inducing cell death. Paradoxically, overexpression of procaspase-3 (PC-3), the low-activity zymogen precursor to caspase-3, has been reported in a variety of cancer types. Until recently, this counterintuitive overexpression of a pro-apoptotic protein in cancer has been puzzling. Recent studies suggest subapoptotic caspase-3 activity may promote oncogenic transformation, a possible explanation for the enigmatic overexpression of PC-3. Herein, the overexpression of PC-3 in cancer and its mechanistic basis is reviewed; collectively, the data suggest the potential for exploitation of PC-3 overexpression with PC-3 activators as a targeted anticancer strategy.
Caspase 3 is the main effector caspase and has a key role in apoptosis. In many types of cancer, including breast, lung, and colon cancer, caspase-3 expression is reduced or absent.
On the other hand, some studies have shown that high levels of caspase-3 expression can be associated with a better prognosis in certain types of cancer, such as breast cancer. This suggests that caspase-3 may play a role in the elimination of cancer cells, and that therapies aimed at activating caspase-3 may be effective in treating certain types of cancer.
Procaspase-3 is a apoptotic marker protein.
Prognostic significance:
• High Cas3 expression: Associated with good prognosis and increased sensitivity to chemotherapy in breast, gastric, lung, and pancreatic cancers.
• Low Cas3 expression: Linked to poor prognosis and increased risk of recurrence in colorectal, hepatocellular carcinoma, ovarian, and prostate cancers.
Scientific Papers found: Click to Expand⟱
2950- PL,    Overview of piperlongumine analogues and their therapeutic potential
- Review, Var, NA
AntiAg↑, neuroP↑, Inflam↓, NO↓, PGE2↓, MMP3↓, MMP13↓, TumCMig↓, TumCI↓, p38↑, JNK↑, NF-kB↑, ROS↑, FOXM1↓, TrxR1↓, GSH↓, Trx↓, cMyc↓, Casp3↑, Bcl-2↓, Mcl-1↓, STAT3↓, AR↓, DNAdam↑,
2970- PL,    Piperlongumine induces apoptosis and autophagy in leukemic cells through targeting the PI3K/Akt/mTOR and p38 signaling pathways
- in-vitro, AML, NA
AntiAg↑, TumCG↓, Apoptosis↑, PI3K↓, Akt↓, mTOR↓, p38↑, Casp3↑,
1944- PL,    Piperlongumine, a Novel TrxR1 Inhibitor, Induces Apoptosis in Hepatocellular Carcinoma Cells by ROS-Mediated ER Stress
- in-vitro, HCC, HUH7 - in-vitro, HCC, HepG2
ER Stress↑, TrxR1↓, ROS↑, eff↓, Bcl-2↓, proCasp3↓, BAX↓, cl‑Casp3↑, TumCCA↑, p‑PERK↑, ATF4↑, TumCG↓, lipid-P↑, selectivity↑,
2944- PL,    Piperlongumine, a Potent Anticancer Phytotherapeutic, Induces Cell Cycle Arrest and Apoptosis In Vitro and In Vivo through the ROS/Akt Pathway in Human Thyroid Cancer Cells
- in-vitro, Thyroid, IHH4 - in-vitro, Thyroid, 8505C - in-vivo, NA, NA
ROS↑, selectivity↑, tumCV↓, TumCCA↑, Apoptosis↑, ERK↑, Akt↓, mTOR↓, neuroP↑, Bcl-2↓, Casp3↑, PARP↑, JNK↑, *toxicity↓, eff↓, TumW↓,
2946- PL,    Piperlongumine, a potent anticancer phytotherapeutic: Perspectives on contemporary status and future possibilities as an anticancer agent
- Review, Var, NA
ROS↑, GSH↓, DNAdam↑, ChemoSen↑, RadioS↑, BioEnh↑, selectivity↑, BioAv↓, eff↑, p‑Akt↓, mTOR↓, GSK‐3β↓, β-catenin/ZEB1↓, HK2↓, Glycolysis↓, Cyt‑c↑, Casp9↑, Casp3↑, Casp7↑, cl‑PARP↑, TrxR↓, ER Stress↑, ATF4↝, CHOP↑, Prx4↑, NF-kB↓, cycD1/CCND1↓, CDK4↓, CDK6↓, p‑RB1↓, RAS↓, cMyc↓, TumCCA↑, selectivity↑, STAT3↓, NRF2↑, HO-1↑, PTEN↑, P-gp↓, MDR1↓, MRP1↓, survivin↓, Twist↓, AP-1↓, Sp1/3/4↓, STAT1↓, STAT6↓, SOX4↑, XBP-1↑, P21↑, eff↑, Inflam↓, COX2↓, IL6↓, MMP9↓, TumMeta↓, TumCI↓, ICAM-1↓, CXCR4↓, VEGF↓, angioG↓, Half-Life↝, BioAv↑,
2948- PL,    The promising potential of piperlongumine as an emerging therapeutics for cancer
- Review, Var, NA
tumCV↓, TumCP↓, TumCI↓, angioG↓, EMT↓, TumMeta↓, *hepatoP↑, *lipid-P↓, *GSH↑, cardioP↑, CycB/CCNB1↓, cycD1/CCND1↓, CDK2↓, CDK1↓, CDK4↓, CDK6↓, PCNA↓, Akt↓, mTOR↓, Glycolysis↓, NF-kB↓, IKKα↓, JAK1↓, JAK2↓, STAT3↓, ERK↓, cFos↓, Slug↓, E-cadherin↑, TOP2↓, P53↑, P21↑, Bcl-2↓, BAX↑, Casp3↑, Casp7↑, Casp8↑, p‑HER2/EBBR2↓, HO-1↑, NRF2↑, BIM↑, p‑FOXO3↓, Sp1/3/4↓, cMyc↓, EGFR↓, survivin↓, cMET↓, NQO1↑, SOD2↑, TrxR↓, MDM2↓, p‑eIF2α↑, ATF4↑, CHOP↑, MDA↑, Ki-67↓, MMP9↓, Twist↓, SOX2↓, Nanog↓, OCT4↓, N-cadherin↓, Vim↓, Snail↓, TumW↓, TumCG↓, HK2↓, RB1↓, IL6↓, IL8↓, SOD1↑, RadioS↑, ChemoSen↑, toxicity↓, Sp1/3/4↓, GSH↓, SOD↑,

Showing Research Papers: 1 to 6 of 6

* 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↓, 3,   HO-1↑, 2,   lipid-P↑, 1,   MDA↑, 1,   NQO1↑, 1,   NRF2↑, 2,   Prx4↑, 1,   ROS↑, 4,   SOD↑, 1,   SOD1↑, 1,   SOD2↑, 1,   Trx↓, 1,   TrxR↓, 2,   TrxR1↓, 2,  

Core Metabolism/Glycolysis ⓘ

cMyc↓, 3,   Glycolysis↓, 2,   HK2↓, 2,  

Cell Death ⓘ

Akt↓, 3,   p‑Akt↓, 1,   Apoptosis↑, 2,   BAX↓, 1,   BAX↑, 1,   Bcl-2↓, 4,   BIM↑, 1,   Casp3↑, 5,   cl‑Casp3↑, 1,   proCasp3↓, 1,   Casp7↑, 2,   Casp8↑, 1,   Casp9↑, 1,   Cyt‑c↑, 1,   JNK↑, 2,   Mcl-1↓, 1,   MDM2↓, 1,   p38↑, 2,   survivin↓, 2,  

Kinase & Signal Transduction ⓘ

p‑HER2/EBBR2↓, 1,   Sp1/3/4↓, 3,  

Transcription & Epigenetics ⓘ

tumCV↓, 2,  

Protein Folding & ER Stress ⓘ

CHOP↑, 2,   p‑eIF2α↑, 1,   ER Stress↑, 2,   p‑PERK↑, 1,   XBP-1↑, 1,  

DNA Damage & Repair ⓘ

DNAdam↑, 2,   P53↑, 1,   PARP↑, 1,   cl‑PARP↑, 1,   PCNA↓, 1,  

Cell Cycle & Senescence ⓘ

CDK1↓, 1,   CDK2↓, 1,   CDK4↓, 2,   CycB/CCNB1↓, 1,   cycD1/CCND1↓, 2,   P21↑, 2,   RB1↓, 1,   p‑RB1↓, 1,   TumCCA↑, 3,  

Proliferation, Differentiation & Cell State ⓘ

cFos↓, 1,   cMET↓, 1,   EMT↓, 1,   ERK↓, 1,   ERK↑, 1,   FOXM1↓, 1,   p‑FOXO3↓, 1,   GSK‐3β↓, 1,   mTOR↓, 4,   Nanog↓, 1,   OCT4↓, 1,   PI3K↓, 1,   PTEN↑, 1,   RAS↓, 1,   SOX2↓, 1,   STAT1↓, 1,   STAT3↓, 3,   STAT6↓, 1,   TOP2↓, 1,   TumCG↓, 3,  

Migration ⓘ

AntiAg↑, 2,   AP-1↓, 1,   E-cadherin↑, 1,   Ki-67↓, 1,   MMP13↓, 1,   MMP3↓, 1,   MMP9↓, 2,   N-cadherin↓, 1,   Slug↓, 1,   Snail↓, 1,   SOX4↑, 1,   TumCI↓, 3,   TumCMig↓, 1,   TumCP↓, 1,   TumMeta↓, 2,   Twist↓, 2,   Vim↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 2,   ATF4↑, 2,   ATF4↝, 1,   EGFR↓, 1,   NO↓, 1,   VEGF↓, 1,  

Barriers & Transport ⓘ

P-gp↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   CXCR4↓, 1,   ICAM-1↓, 1,   IKKα↓, 1,   IL6↓, 2,   IL8↓, 1,   Inflam↓, 2,   JAK1↓, 1,   JAK2↓, 1,   NF-kB↓, 2,   NF-kB↑, 1,   PGE2↓, 1,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 1,   CDK6↓, 2,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 1,   BioAv↑, 1,   BioEnh↑, 1,   ChemoSen↑, 2,   eff↓, 2,   eff↑, 2,   Half-Life↝, 1,   MDR1↓, 1,   MRP1↓, 1,   RadioS↑, 2,   selectivity↑, 4,  

Clinical Biomarkers ⓘ

AR↓, 1,   EGFR↓, 1,   FOXM1↓, 1,   p‑HER2/EBBR2↓, 1,   IL6↓, 2,   Ki-67↓, 1,  

Functional Outcomes ⓘ

cardioP↑, 1,   neuroP↑, 2,   toxicity↓, 1,   TumW↓, 2,  
Total Targets: 138

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

GSH↑, 1,   lipid-P↓, 1,  

Functional Outcomes ⓘ

hepatoP↑, 1,   toxicity↓, 1,  
Total Targets: 4

Scientific Paper Hit Count for: Casp3, CPP32, Cysteinyl aspartate specific proteinase-3
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#:42  State#:%  Dir#:2
  wNotes=0  sortOrder:rid,rpid

 

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