Database Query Results : Parthenolide, , Trx

PTL, Parthenolide: Click to Expand ⟱
Features:
Parthenolide is a naturally occurring sesquiterpene lactone derived from the medicinal plant feverfew (Tanacetum parthenium).
-Micheliolide (MCL) is converted readily from parthenolide (PTL), and has better stability and solubility than PTL
-Parthenolide is a natural compound used to treat migraines and arthritis and found to act as a potent NF-κB signaling inhibitor.

Main activities include:
-Inhibition of NF-κB Signaling:
-Induction of Oxidative Stress (ROS): oxidative stress can overwhelm the antioxidant defenses of the cancer cells, leading to cellular damage and death
-Parthenolide can interfere with STAT3 signaling, inhibiting the transcription of genes that favor tumor growth and resistance to apoptosis.
-Modulation of the MAPK/ERK Pathway:
-Impact on the JNK Pathway:
-Parthenolide has been shown to target cancer stem cells

Rank Pathway / Target Axis Direction Primary Effect Notes / Cancer Relevance Ref
1 NF-κB DNA-binding (p65/RelA Cys38 alkylation) ↓ NF-κB DNA binding Suppresses pro-survival transcription Direct mechanism: parthenolide inhibits NF-κB most likely by alkylating p65 at Cys38, reducing DNA binding (ref)
2 Thioredoxin reductase (TrxR1 / TrxR2) ↓ TrxR activity Redox buffering collapse Parthenolide directly targets TrxR1/TrxR2 (selenocysteine-containing enzymes) and inhibits function (ref)
3 ROS accumulation (superoxide / oxidative stress) ↑ ROS Upstream cytotoxic trigger Same TrxR-targeting study shows TrxR inhibition shifts redox state and drives ROS accumulation leading to apoptosis (ref)
4 Mitochondrial integrity (ΔΨm) ↓ ΔΨm Mitochondrial dysfunction Parthenolide increases ROS and is reported with a combined ΔΨm reduction accompanying apoptosis across cancer cell lines (ref)
5 Intrinsic apoptosis (caspase-3 activation) ↑ caspase-3 Programmed cell death Parthenolide treatment associated with mitochondrial membrane depolarization and caspase-3 activation in cancer cells (ref)
6 STAT3 signaling (via JAK2 covalent inhibition) ↓ STAT3 phosphorylation/signaling Reduced survival / migration programs Parthenolide covalently modifies JAK2 cysteines, suppressing kinase activity and inhibiting STAT3 signaling (ref)
7 AML stem cell targeting (LSC vulnerability; regimen context) ↓ AML stem cell survival Stem/progenitor depletion Parthenolide-based regimen (parthenolide + 2DG + temsirolimus) demonstrates potent targeting of AML stem cells (ref)
8 In vivo anti-tumor effect (xenograft; parthenolide analog evidence) ↓ tumor growth Demonstrated efficacy (derivative) Note: this is for an orally bioavailable parthenolide analog (DMAPT), not native parthenolide (ref)


Trx, Thioredoxin: Click to Expand ⟱
Source:
Type: protein
Trx is a small protein that acts as a reducing agent, donating electrons to reduce oxidized proteins and other molecules.
Trx is overexpressed in various types of cancer, including breast, lung, colon, and prostate cancer.

- Cytosolic thioredoxin (TRX-1) and mitochondrial thioredoxin (TRX-2).

- Thioredoxin is a pivotal redox regulator that protects cells from oxidative stress and supports survival and proliferation.

- There is interest in combining thioredoxin inhibitors with conventional chemotherapy or radiotherapy to sensitize tumors to oxidative stress and improve treatment efficacy.
Scientific Papers found: Click to Expand⟱
1987- PTL,  Rad,    A NADPH oxidase dependent redox signaling pathway mediates the selective radiosensitization effect of parthenolide in prostate cancer cells
- in-vitro, Pca, PC3 - in-vitro, Nor, PrEC
selectivity↑, parthenolide (PN), a sesquiterpene lactone, selectively exhibits a radiosensitization effect on prostate cancer PC3 cells but not on normal prostate epithelial PrEC cells.
RadioS↑,
ROS↑, oxidative stress in PC3 cells but not in PrEC cells
*ROS∅, oxidative stress in PC3 cells but not in PrEC cells
NADPH↑, In PC3 but not PrEC cells, PN activates NADPH oxidase leading to a decrease in the level of reduced thioredoxin, activation of PI3K/Akt and consequent FOXO3a phosphorylation, which results in the downregulation of FOXO3a targets, MnSOD, CAT
Trx↓,
PI3K↑,
Akt↑,
p‑FOXO3↓, downregulation of FOXO3a targets, antioxidant enzyme manganese superoxide dismutase (MnSOD) and catalase
SOD2↓, MnSOD
Catalase↓,
radioP↑, when combined with radiation, PN further increases ROS levels in PC3 cells, while it decreases radiation-induced oxidative stress in PrEC cells
*NADPH∅, Parthenolide activates NADPH oxidase in PC3 cells but not in PrEC cells
*GSH↑, increases glutathione (GSH) in PrEC cells(normal cells)
*GSH/GSSG↑, GSH/GSSG ratio is not significantly changed by parthenolide in PC3 cells but is increased 2.4 fold in PrEC cells (normal cells)
*NRF2↑, The induction of GSH may be due to the activation of the Nrf2/ARE (antioxidant/electrophile response element) pathway

1986- PTL,    Modulation of Cell Surface Protein Free Thiols: A Potential Novel Mechanism of Action of the Sesquiterpene Lactone Parthenolide
- in-vitro, NA, NA
JNK↑, parthenolide mediated activation of JNK
ROS↑, parthenolide induced generation of intracellular reactive oxygen species
eff↓, Parthenolide Cytotoxicity Is Blocked by Thiol Antioxidants
NF-kB↓, parthenolide has been shown to induce malignant cell death by inhibiting NFκB activation and/or activating JNK
Trx↓, thioredoxin pull-down

1985- PTL,    KEAP1 Is a Redox Sensitive Target That Arbitrates the Opposing Radiosensitive Effects of Parthenolide in Normal and Cancer Cells
- in-vitro, Pca, LNCaP - in-vitro, Pca, DU145 - in-vitro, Nor, PrEC - in-vivo, NA, NA
ROS↑, parthenolide enhances ROS production in prostate cancer cells through activation of NADPH oxidase
NADPH↑,
RadioS↑, In vivo, parthenolide increases radiosensitivity of mouse xenograft tumors but protects normal prostate and bladder tissues against radiation-induced injury
radioP↑, DMAPT, the water soluble prodrug of parthenolide, is a promising agent for selectively enhancing the sensitivity of prostate cancer cells to radiation while protecting normal tissues from damage caused by radiation.
Trx↓, causes oxidation of thioredoxin (TrX) in prostate cancer cells
*ox-Keap1↑, three normal cell lines, parthenolide increased the oxidized form of Keap1 but decreased the reduced form of Keap1
ox-Keap1↓, results from the three cancer cell lines appeared to be completely opposite to results observed in normal cells treated with parthenolide
rd-Keap1↑, in vivo results show that parthenolide decreased the oxidized form of Keap1 but increased the reduced form of Keap1 in the tumors
*NRF2↑, Oxidization of Keap1 leads to activation of the Nrf2 pro-survival pathway in normal cells. Nrf2 pathway is a major mechanism by which parthenolide protects normal cells against radiation injury
NRF2∅, but no changes were observed in the three cancer cell lines.
NF-kB↓, It has been reported that parthenolide is a potent inhibitor of NF-κB


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 3

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Catalase↓, 1,   ox-Keap1↓, 1,   rd-Keap1↑, 1,   NRF2∅, 1,   ROS↑, 3,   SOD2↓, 1,   Trx↓, 3,  

Core Metabolism/Glycolysis ⓘ

NADPH↑, 2,  

Cell Death ⓘ

Akt↑, 1,   JNK↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

p‑FOXO3↓, 1,   PI3K↑, 1,  

Immune & Inflammatory Signaling ⓘ

NF-kB↓, 2,  

Drug Metabolism & Resistance ⓘ

eff↓, 1,   RadioS↑, 2,   selectivity↑, 1,  

Functional Outcomes ⓘ

radioP↑, 2,  
Total Targets: 17

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

GSH↑, 1,   GSH/GSSG↑, 1,   ox-Keap1↑, 1,   NRF2↑, 2,   ROS∅, 1,  

Core Metabolism/Glycolysis ⓘ

NADPH∅, 1,  
Total Targets: 6

Scientific Paper Hit Count for: Trx, Thioredoxin
3 Parthenolide
1 Radiotherapy/Radiation
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#:8  Target#:824  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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