Piperlongumine / HO-1 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)


HO-1, HMOX1: Click to Expand ⟱
Source:
Type:
(Also known as Hsp32 and HMOX1)
HO-1 is the common abbreviation for the protein (heme oxygenase‑1) produced by the HMOX1 gene.
HO-1 is an enzyme that plays a crucial role in various cellular processes, including the breakdown of heme, a toxic molecule. Research has shown that HO-1 is involved in the development and progression of cancer.
-widely regarded as having antioxidant and cytoprotective effects
-The overall activity of HO‑1 helps to reduce the pro‐oxidant load (by degrading free heme, a pro‑oxidant) and to generate molecules (like bilirubin) that can protect cells from oxidative damage

Studies have found that HO-1 is overexpressed in various types of cancer, including lung, breast, colon, and prostate cancer. The overexpression of HO-1 in cancer cells can contribute to their survival and proliferation by:
  Reducing oxidative stress and inflammation
  Promoting angiogenesis (the formation of new blood vessels)
  Inhibiting apoptosis (programmed cell death)
  Enhancing cell migration and invasion
When HO-1 is at a normal level, it mainly exerts an antioxidant effect, and when it is excessively elevated, it causes an accumulation of iron ions.

A proper cellular level of HMOX1 plays an antioxidative function to protect cells from ROS toxicity. However, its overexpression has pro-oxidant effects to induce ferroptosis of cells, which is dependent on intracellular iron accumulation and increased ROS content upon excessive activation of HMOX1.

-Curcumin   Activates the Nrf2 pathway leading to HO‑1 induction; known for its anti‑inflammatory and antioxidant effects.
-Resveratrol  Induces HO‑1 via activation of SIRT1/Nrf2 signaling; exhibits antioxidant and cardioprotective properties.
-Quercetin   Activates Nrf2 and related antioxidant pathways; contributes to anti‑oxidative and anti‑inflammatory responses.
-EGCG     Promotes HO‑1 expression through activation of the Nrf2/ARE pathway; also exhibits anti‑inflammatory and anticancer properties.
-Sulforaphane One of the most potent natural HO‑1 inducers; triggers Nrf2 nuclear translocation and upregulates a battery of phase II detoxifying enzymes.
-Luteolin    Induces HO‑1 via Nrf2 activation; may also exert anti‑inflammatory and neuroprotective effects in various cell models.
-Apigenin   Has been reported to induce HO‑1 expression partly via the MAPK and Nrf2 pathways; also known for anti‑inflammatory and anticancer activities.
Scientific Papers found: Click to Expand⟱
2954- PL,    The metabolites from traditional Chinese medicine targeting ferroptosis for cancer therapy
- Review, Var, NA
NRF2↑, ROS↑, ER Stress↑, MAPK↑, CHOP↑, selectivity↑, Keap1↝, HO-1↑, Ferroptosis↑,
2955- PL,    Heme Oxygenase-1 Determines the Differential Response of Breast Cancer and Normal Cells to Piperlongumine
- in-vitro, BC, MCF-7 - in-vitro, Nor, MCF10
ROS?, *ROS∅, other⇅, HO-1↑, *HO-1↑, NRF2↑, Keap1↓, cl‑PARP↑, selectivity↑, GSH↓, GSSG↑,
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 4 of 4

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 4

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Ferroptosis↑, 1,   GSH↓, 3,   GSSG↑, 1,   HO-1↑, 4,   Keap1↓, 1,   Keap1↝, 1,   MDA↑, 1,   NQO1↑, 1,   NRF2↑, 4,   Prx4↑, 1,   ROS?, 1,   ROS↑, 2,   SOD↑, 1,   SOD1↑, 1,   SOD2↑, 1,   TrxR↓, 2,  

Core Metabolism/Glycolysis ⓘ

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

Cell Death ⓘ

Akt↓, 1,   p‑Akt↓, 1,   BAX↑, 1,   Bcl-2↓, 1,   BIM↑, 1,   Casp3↑, 2,   Casp7↑, 2,   Casp8↑, 1,   Casp9↑, 1,   Cyt‑c↑, 1,   Ferroptosis↑, 1,   MAPK↑, 1,   MDM2↓, 1,   survivin↓, 2,  

Kinase & Signal Transduction ⓘ

p‑HER2/EBBR2↓, 1,   Sp1/3/4↓, 3,  

Transcription & Epigenetics ⓘ

other⇅, 1,   tumCV↓, 1,  

Protein Folding & ER Stress ⓘ

CHOP↑, 3,   p‑eIF2α↑, 1,   ER Stress↑, 2,   XBP-1↑, 1,  

DNA Damage & Repair ⓘ

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

Proliferation, Differentiation & Cell State ⓘ

cFos↓, 1,   cMET↓, 1,   EMT↓, 1,   ERK↓, 1,   p‑FOXO3↓, 1,   GSK‐3β↓, 1,   mTOR↓, 2,   Nanog↓, 1,   OCT4↓, 1,   PTEN↑, 1,   RAS↓, 1,   SOX2↓, 1,   STAT1↓, 1,   STAT3↓, 2,   STAT6↓, 1,   TOP2↓, 1,   TumCG↓, 1,  

Migration ⓘ

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

Angiogenesis & Vasculature ⓘ

angioG↓, 2,   ATF4↑, 1,   ATF4↝, 1,   EGFR↓, 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↓, 1,   JAK1↓, 1,   JAK2↓, 1,   NF-kB↓, 2,  

Hormonal & Nuclear Receptors ⓘ

CDK6↓, 2,  

Drug Metabolism & Resistance ⓘ

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

Clinical Biomarkers ⓘ

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

Functional Outcomes ⓘ

cardioP↑, 1,   toxicity↓, 1,   TumW↓, 1,  
Total Targets: 119

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

GSH↑, 1,   HO-1↑, 1,   lipid-P↓, 1,   ROS∅, 1,  

Functional Outcomes ⓘ

hepatoP↑, 1,  
Total Targets: 5

Scientific Paper Hit Count for: HO-1, HMOX1
4 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#:597  State#:%  Dir#:2
  wNotes=0  sortOrder:rid,rpid

 

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