condition found tbRes List
Part, 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


ROS, Reactive Oxygen Species: Click to Expand ⟱
Source: HalifaxProj (inhibit)
Type:
Reactive oxygen species (ROS) are highly reactive molecules that contain oxygen and can lead to oxidative stress in cells. They play a dual role in cancer biology, acting as both promoters and suppressors of cancer.
ROS can cause oxidative damage to DNA, leading to mutations that may contribute to cancer initiation and progression. So normally you want to inhibit ROS to prevent cell mutations.
However excessive ROS can induce apoptosis (programmed cell death) in cancer cells, potentially limiting tumor growth. Chemotherapy typically raises ROS.

"Reactive oxygen species (ROS) are two electron reduction products of oxygen, including superoxide anion, hydrogen peroxide, hydroxyl radical, lipid peroxides, protein peroxides and peroxides formed in nucleic acids 1. They are maintained in a dynamic balance by a series of reduction-oxidation (redox) reactions in biological systems and act as signaling molecules to drive cellular regulatory pathways."
"During different stages of cancer formation, abnormal ROS levels play paradoxical roles in cell growth and death 8. A physiological concentration of ROS that maintained in equilibrium is necessary for normal cell survival. Ectopic ROS accumulation promotes cell proliferation and consequently induces malignant transformation of normal cells by initiating pathological conversion of physiological signaling networks. Excessive ROS levels lead to cell death by damaging cellular components, including proteins, lipid bilayers, and chromosomes. Therefore, both scavenging abnormally elevated ROS to prevent early neoplasia and facilitating ROS production to specifically kill cancer cells are promising anticancer therapeutic strategies, in spite of their contradictoriness and complexity."
"ROS are the collection of derivatives of molecular oxygen that occur in biology, which can be categorized into two types, free radicals and non-radical species. The non-radical species are hydrogen peroxide (H 2O 2 ), organic hydroperoxides (ROOH), singlet molecular oxygen ( 1 O 2 ), electronically excited carbonyl, ozone (O3 ), hypochlorous acid (HOCl, and hypobromous acid HOBr). Free radical species are super-oxide anion radical (O 2•−), hydroxyl radical (•OH), peroxyl radical (ROO•) and alkoxyl radical (RO•) [130]. Any imbalance of ROS can lead to adverse effects. H2 O 2 and O 2 •− are the main redox signalling agents. The cellular concentration of H2 O 2 is about 10−8 M, which is almost a thousand times more than that of O2 •−".
"Radicals are molecules with an odd number of electrons in the outer shell [393,394]. A pair of radicals can be formed by breaking a chemical bond or electron transfer between two molecules."

Recent investigations have documented that polyphenols with good antioxidant activity may exhibit pro-oxidant activity in the presence of copper ions, which can induce apoptosis in various cancer cell lines but not in normal cells. "We have shown that such cell growth inhibition by polyphenols in cancer cells is reversed by copper-specific sequestering agent neocuproine to a significant extent whereas iron and zinc chelators are relatively ineffective, thus confirming the role of endogenous copper in the cytotoxic action of polyphenols against cancer cells. Therefore, this mechanism of mobilization of endogenous copper." > Ions could be one of the important mechanisms for the cytotoxic action of plant polyphenols against cancer cells and is possibly a common mechanism for all plant polyphenols. In fact, similar results obtained with four different polyphenolic compounds in this study, namely apigenin, luteolin, EGCG, and resveratrol, strengthen this idea.
Interestingly, the normal breast epithelial MCF10A cells have earlier been shown to possess no detectable copper as opposed to breast cancer cells [24], which may explain their resistance to polyphenols apigenin- and luteolin-induced growth inhibition as observed here (Fig. 1). We have earlier proposed [25] that this preferential cytotoxicity of plant polyphenols toward cancer cells is explained by the observation made several years earlier, which showed that copper levels in cancer cells are significantly elevated in various malignancies. Thus, because of higher intracellular copper levels in cancer cells, it may be predicted that the cytotoxic concentrations of polyphenols required would be lower in these cells as compared to normal cells."

Majority of ROS are produced as a by-product of oxidative phosphorylation, high levels of ROS are detected in almost all cancers.
-It is well established that during ER stress, cytosolic calcium released from the ER is taken up by the mitochondrion to stimulate ROS overgeneration and the release of cytochrome c, both of which lead to apoptosis.

Note: Products that may raise ROS can be found using this database, by:
Filtering on the target of ROS, and selecting the Effect Direction of ↑

Targets to raise ROS (to kill cancer cells):
• NADPH oxidases (NOX): NOX enzymes are involved in the production of ROS.
    -Targeting NOX enzymes can increase ROS levels and induce cancer cell death.
    -eNOX2 inhibition leads to a high NADH/NAD⁺ ratio which can lead to increased ROS
• Mitochondrial complex I: Inhibiting can increase ROS production
• P53: Activating p53 can increase ROS levels(by inducing the expression of pro-oxidant genes)
• Nrf2: regulates the expression of antioxidant genes. Inhibiting Nrf2 can increase ROS levels
• Glutathione (GSH): an antioxidant. Depleting GSH can increase ROS levels
• Catalase: Catalase converts H2O2 into H2O+O. Inhibiting catalase can increase ROS levels
• SOD1: converts superoxide into hydrogen peroxide. Inhibiting SOD1 can increase ROS levels
• PI3K/AKT pathway: regulates cell survival and metabolism. Inhibiting can increase ROS levels
• HIF-1α: regulates genes involved in metabolism and angiogenesis. Inhibiting HIF-1α can increase ROS
• Glycolysis: Inhibiting glycolysis can increase ROS levels • Fatty acid oxidation: Cancer cells often rely on fatty acid oxidation for energy production.
-Inhibiting fatty acid oxidation can increase ROS levels
• ER stress: Endoplasmic reticulum (ER) stress can increase ROS levels
• Autophagy: process by which cells recycle damaged organelles and proteins.
-Inhibiting autophagy can increase ROS levels and induce cancer cell death.
• KEAP1/Nrf2 pathway: regulates the expression of antioxidant genes.
    -Inhibiting KEAP1 or activating Nrf2 can increase ROS levels and induce cancer cell death.
• DJ-1: regulates the expression of antioxidant genes. Inhibiting DJ-1 can increase ROS levels
• PARK2: regulates the expression of antioxidant genes. Inhibiting PARK2 can increase ROS levels
• SIRT1:regulates the expression of antioxidant genes. Inhibiting SIRT1 can increase ROS levels
• AMPK: regulates energy metabolism and can increase ROS levels when activated.
• mTOR: regulates cell growth and metabolism. Inhibiting mTOR can increase ROS levels
• HSP90: regulates protein folding and can increase ROS levels when inhibited.
• Proteasome: degrades damaged proteins. Inhibiting the proteasome can increase ROS levels
• Lipid peroxidation: a process by which lipids are oxidized, leading to the production of ROS.
    -Increasing lipid peroxidation can increase ROS levels
• Ferroptosis: form of cell death that is regulated by iron and lipid peroxidation.
    -Increasing ferroptosis can increase ROS levels
• Mitochondrial permeability transition pore (mPTP): regulates mitochondrial permeability.
    -Opening the mPTP can increase ROS levels
• BCL-2 family proteins: regulate apoptosis and can increase ROS levels when inhibited.
• Caspase-independent cell death: a form of cell death that is regulated by ROS.
    -Increasing caspase-independent cell death can increase ROS levels
• DNA damage response: regulates the repair of DNA damage. Increasing DNA damage can increase ROS
• Epigenetic regulation: process by which gene expression is regulated.
    -Increasing epigenetic regulation can increase ROS levels

-PKM2, but not PKM1, can be inhibited by direct oxidation of cysteine 358 as an adaptive response to increased intracellular reactive oxygen species (ROS)

ProOxidant Strategy:(inhibit the Melavonate Pathway (likely will also inhibit GPx)
-HydroxyCitrate (HCA) found as supplement online and typically used in a dose of about 1.5g/day or more
-Atorvastatin typically 40-80mg/day
-Dipyridamole typically 200mg 2x/day
-Lycopene typically 100mg/day range

Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy

Scientific Papers found: Click to Expand⟱
1983- Part,    Targeting thioredoxin reductase by micheliolide contributes to radiosensitizing and inducing apoptosis of HeLa cells
- in-vitro, Cerv, HeLa
eff↑, micheliolide (MCL) is converted readily from parthenolide (PTL), and has better stability and solubility than PTL
TrxR↓, MCL-targeted inhibition of TrxR
ROS↑, promotes oxidative stress-mediated HeLa cell apoptosis
RadioS↑, sensitizes ionizing radiation (IR) treatment

1984- Part,    Targeting Thioredoxin Reductase by Parthenolide Contributes to Inducing Apoptosis of HeLa Cells
- in-vitro, Cerv, HeLa
AntiCan↑, PTL demonstrates potent anticancer efficacy in numerous types of malignant cells,
TrxR1↓, PTL interacts with both cytosolic thioredoxin reductase (TrxR1) and mitochondrial thioredoxin reductase (TrxR2)
TrxR2↓,
ROS↑, elicit reactive oxygen species-mediated apoptosis in HeLa cells
Apoptosis↑,
eff↓, blocked by pretreatment of the cells with NAC
eff↑, depletion of cellular GSH by pretreatment of the cells with BSO enhances the cytotoxicity of PTL

1985- Part,    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

1986- Part,    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

1987- Part,  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

1988- Part,    Parthenolide Induces ROS-Mediated Apoptosis in Lymphoid Malignancies
- in-vitro, lymphoma, NCI-H929
NF-kB↓, Parthenolide is a natural compound used to treat migraines and arthritis and found to act as a potent NF-κB signaling inhibitor.
ROS↑, parthenolide promoted cell death by apoptosis with significant ROS increase
GSH↓, GSH decrease combined with a ΔΨmit reduction across all studied cell line
MMP↓,
GPx1↓, parthenolide significantly decreased GPX1 expression

1989- Part,    Parthenolide and Its Soluble Analogues: Multitasking Compounds with Antitumor Properties
- Review, Var, NA
eff↑, therapeutical potential of PN has been increased by chemical design and synthesis of more soluble analogues including dimethylaminoparthenolide (DMAPT).
NF-kB↓, these compounds not only inhibit prosurvival transcriptional factors such as NF-κB and STATs
STAT↓,
ROS↑, increasing intracellular reactive oxygen species (ROS) production
Inflam↓, anti-inflammatory action of PN has been widely considered a consequence of its inhibitory effect on the transcription factors belonging to NF-κB family
Wnt↓, PN was recently shown to inhibit Wnt signaling by decreasing the levels of the transcription factors TCF4/LEF1
TCF-4↓,
LEF1↓,
GSH↓, Wen et al., who found that PN-induced apoptosis in hepatoma cells was accompanied with depletion of glutathione (GSH), generation of ROS, reduction of mitochondrial transmembrane potential and activation of caspases.
MMP↓,
Casp↑,
eff↓, These effects were effectively abrogated by the antioxidant N-acetyl-l-cysteine (NAC) and enhanced by the GSH synthesis inhibitor buthionine sulfoximine (BSO) confirming the role of oxidative stress in PN-induced apoptosis
CSCs↓, several studies showing the effect of PN in reducing the presence of CSCs in solid and hematological tumors

1990- Part,    Parthenolide alleviates cognitive dysfunction and neurotoxicity via regulation of AMPK/GSK3β(Ser9)/Nrf2 signaling pathway
- in-vitro, AD, PC12
*Apoptosis↓, curtail apoptosis, reduce reactive oxygen species (ROS) production, and restore mitochondrial membrane potential in PC12 cells
*ROS↓,
*MMP↓,
*memory↑, PTN treatment demonstrates a capacity to ameliorate deficits in spatial learning and memory in the 3 ×Tg-AD murine model
*eff↑, PTN's therapeutic efficacy surpasses that of a clinical agent, donepezil

1991- Part,    A novel SLC25A1 inhibitor, parthenolide, suppresses the growth and stemness of liver cancer stem cells with metabolic vulnerability
- in-vitro, Liver, HUH7
TumCCA↑, PTL stimulated cell cycle arrest at the G1 phase, induced apoptosis, and decreased the stemness of LCSCs
Apoptosis↑,
CSCs↓,
ROS↑, PTL caused the production of ROS and the reduction of oxidative phosphorylation (OXPHOS) and mitochondrial membrane potential (MMP) levels of LCSCs
OXPHOS↓, PTL inhibited OXPHOS levels
MMP↓,
SLC25A1↓, PTL decreased SLC25A1 expression at the mRNA level
IDH2↓, inhibition of SLC25A1 synergistically decreased the expression of IDH2

1992- Part,    Parthenolide induces ROS-dependent cell death in human gastric cancer cell
- in-vitro, BC, MGC803
TumCCA↑, Parthenolide induced cell cycle arrest at the G1 and S stages.
Casp↑, Parthenolide-induced caspase-dependent apoptosis and necroptosis were caused by the activation of RIP, RIP3 and MLKL
Apoptosis↑,
Necroptosis↑,
RIP1↓,
RIP3↑,
MLKL↑,
ROS↑, MGC-803 cells showed a response to ROS and oxidative stress after PN treatment.
eff↓, ROS and cytotoxicity induced by PN were significantly attenuated by a ROS scavenger catalase.

1993- Part,    Parthenolide induces apoptosis and autophagy through the suppression of PI3K/Akt signaling pathway in cervical cancer
- in-vitro, Cerv, HeLa
tumCV↓, Parthenolide inhibits HeLa cell viability in a dose dependent-manner and was confirmed by MTT assay.
TumAuto↑, Parthenolide (6 µM) induces mitochondrial-mediated apoptosis and autophagy by activation of caspase-3, upregulation of Bax, Beclin-1, ATG5, ATG3
Casp3↑,
BAX↑,
Beclin-1↑,
ATG3↑,
ATG5↑,
Bcl-2↓, and down-regulation of Bcl-2 and mTOR
mTOR↓,
PI3K↓, inhibits PI3K and Akt expression through activation of PTEN expression.
Akt↓,
PTEN↑,
ROS↑, parthenolide induces generation of reactive oxygen species that leads to the loss of mitochondrial membrane potential
MMP↓,

1994- Part,    Parthenolide Inhibits Tumor Cell Growth and Metastasis in Melanoma A2058 Cells
- in-vitro, Melanoma, A2058 - in-vitro, Nor, L929
tumCV↓, PAR significantly reduced the viability of A2058 cancer cells
selectivity?, demonstrating greater potency against cancer cells compared to normal L929 cells (IC50: 20 μM vs. 27 μM after 24h
ROS?, PAR increased ROS production
BAX↑, elevated mRNA expression of pro-apoptotic Bax and NME1 genes
TumCCA?, PAR induced apoptosis and cell cycle arrest in A2058 cells, as evidenced by the increased proportion of cells in the late apoptotic phase and sub-G1 cell cycle arrest
MMP2↓, MMP-2 and MMP-9 mRNA and protein expressions, gelatinase activity, and the migration of A2058 cells were also decreased by PAR
MMP9↓,
TumCMig↓,
eff↑, These results, along with the synergic effect with dacarbazine, indicated that PAR may have the potential to be a therapeutic drug for melanoma by triggering apoptosis and suppressing invasion and migration.

1995- Part,    The protective effect of parthenolide in an in vitro model of Parkinson's disease through its regulation of nuclear factor-kappa B and oxidative stress
- in-vitro, Park, SH-SY5Y
*Apoptosis↓, PTN reduced apoptosis induced by 6-OHDA.
*ROS↓, PTN also reduced the ROS levels raised by 6-OHDA
*BAX↓, PTN decreased the expression of Bax, p53, NF-κB, and p-NF-κB that were increased by treatment with 6-OHDA.
*NF-kB↓,
*P53↓,
*p‑NF-kB↓,

1996- Part,    Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells
- in-vitro, CRC, COLO205
Apoptosis↑, parthenolide has shown to induce apoptosis in cancer cells
GSH↓, Parthenolide rapidly depleted intracellular thiols, including both free glutathione (GSH) and protein thiols.
ROS↑, ncreases in intracellular reactive oxygen species (ROS) and calcium levels
Ca+2↑,
GRP78/BiP↑, Increased expression of GRP78 protein, a marker for endoplasmic reticulum stress was also detected
ER Stress↑,
eff↓, pretreatment with N-acetylcysteine, a precursor of GSH synthesis, protected the cells from parthenolide-induced thiol depletion, ROS production, cytosolic calcium increase and completely blocked parthenolide-induced apoptosis.
eff↑, pretreatment of buthionine sulfoximine, an inhibitor of GSH synthesis sensitized the cell to apoptosis
Thiols↓, Parthenolide rapidly depleted intracellular thiols


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 14

Results for Effect on Cancer/Diseased Cells:
Akt↓,1,   Akt↑,1,   AntiCan↑,1,   Apoptosis↑,4,   ATG3↑,1,   ATG5↑,1,   BAX↑,2,   Bcl-2↓,1,   Beclin-1↑,1,   Ca+2↑,1,   Casp↑,2,   Casp3↑,1,   Catalase↓,1,   CSCs↓,2,   eff↓,5,   eff↑,5,   ER Stress↑,1,   p‑FOXO3↓,1,   GPx1↓,1,   GRP78/BiP↑,1,   GSH↓,3,   IDH2↓,1,   Inflam↓,1,   JNK↑,1,   ox-Keap1↓,1,   rd-Keap1↑,1,   LEF1↓,1,   MLKL↑,1,   MMP↓,4,   MMP2↓,1,   MMP9↓,1,   mTOR↓,1,   NADPH↑,2,   Necroptosis↑,1,   NF-kB↓,4,   NRF2∅,1,   OXPHOS↓,1,   PI3K↓,1,   PI3K↑,1,   PTEN↑,1,   radioP↑,2,   RadioS↑,3,   RIP1↓,1,   RIP3↑,1,   ROS?,1,   ROS↑,11,   selectivity?,1,   selectivity↑,1,   SLC25A1↓,1,   SOD2↓,1,   STAT↓,1,   TCF-4↓,1,   Thiols↓,1,   Trx↓,3,   TrxR↓,1,   TrxR1↓,1,   TrxR2↓,1,   TumAuto↑,1,   TumCCA?,1,   TumCCA↑,2,   TumCMig↓,1,   tumCV↓,2,   Wnt↓,1,  
Total Targets: 63

Results for Effect on Normal Cells:
Apoptosis↓,2,   BAX↓,1,   eff↑,1,   GSH↑,1,   GSH/GSSG↑,1,   ox-Keap1↑,1,   memory↑,1,   MMP↓,1,   NADPH∅,1,   NF-kB↓,1,   p‑NF-kB↓,1,   NRF2↑,2,   P53↓,1,   ROS↓,2,   ROS∅,1,  
Total Targets: 15

Scientific Paper Hit Count for: ROS, Reactive Oxygen Species
14 Parthenolide
1 Radiotherapy/Radiation
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:8  Target#:275  State#:%  Dir#:%
wNotes=on sortOrder:rid,rpid

 

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