Piperlongumine / GSH 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↓">GSH↓ Catalase↓ HO1↓ GPx↓
- Very little indication of raising AntiOxidant defense in Normal Cells: GSH↑">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)

GSH, Glutathione: Click to Expand ⟱

Source:

Type:

Glutathione (GSH) is a thiol antioxidant that scavenges reactive oxygen species (ROS), resulting in the formation of oxidized glutathione (GSSG). Decreased amounts of GSH and a decreased GSH/GSSG ratio in tissues are biomarkers of oxidative stress.
Glutathione is a powerful antioxidant found in every cell of the body, composed of three amino acids: cysteine, glutamine, and glycine. It plays a crucial role in protecting cells from oxidative stress, detoxifying harmful substances, and supporting the immune system.
cancer cells can have elevated levels of glutathione, which may help them survive in the oxidative environment created by the immune response and chemotherapy. This can make cancer cells more resistant to treatment.
While glutathione can be obtained from certain foods (like fruits, vegetables, and meats), its absorption from supplements is debated. Some people take N-acetylcysteine (NAC) or other precursors to boost glutathione levels, but the effects on cancer prevention or treatment are still being studied.
Depleting glutathione (GSH) to raise reactive oxygen species (ROS) is a strategy that has been explored in cancer research and therapy.
Many cancer cells have altered redox states and may rely on GSH to survive. Increasing ROS levels can induce stress in these cells, potentially leading to cell death.
Certain drugs and compounds can deplete GSH levels. For example, agents like buthionine sulfoximine (BSO) inhibit the synthesis of GSH, leading to its depletion.
Cancer cells tend to exhibit higher levels of intracellular GSH, possibly as an adaptive response to a higher metabolism and thus higher steady-state levels of reactive oxygen species (ROS).

"...intracellular glutathione (GSH) exhibits an astounding antioxidant activity in scavenging reactive oxygen species (ROS)..."
"Cancer cells have a high level of GSH compared to normal cells."
"...cancer cells are affluent with high antioxidant levels, especially with GSH, whose appearance at an elevated concentration of ∼10 mM (10 times less in normal cells) detoxifies the cancer cells." "Therefore, GSH depletion can be assumed to be the key strategy to amplify the oxidative stress in cancer cells, enhancing the destruction of cancer cells by fruitful cancer therapy."

The loss of GSH is broadly known to be directly related to the apoptosis progression.

Scientific Papers found: Click to Expand⟱

1953-

PL,

Designing piperlongumine-directed anticancer agents by an electrophilicity-based prooxidant strategy: A mechanistic investigation

in-vitro,

Lung,

A549

in-vitro,

Nor,

WI38

ROS↑, selectivity↑, TrxR↓, TumCCA↑, GSH?, H2O2↑,

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 ⓘ

GSH?, 1, H2O2↑, 1, ROS↑, 1, TrxR↓, 1,

Cell Cycle & Senescence ⓘ

TumCCA↑, 1,

Drug Metabolism & Resistance ⓘ

selectivity↑, 1,
Total Targets: 6

Pathway results for Effect on Normal Cells:

Total Targets: 0

Scientific Paper Hit Count for: GSH, Glutathione

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