condition found tbRes List
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


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⟱
2952- PL,    Piperlongumine suppresses bladder cancer invasion via inhibiting epithelial mesenchymal transition and F-actin reorganization
- in-vitro, Bladder, T24 - in-vivo, Bladder, NA
TumCP↓, PL significantly suppressed bladder cancer cell proliferation, the transition of G2/M phase to next phase, migration/invasion in vitro and bladder cancer growth/development in vivo
TumCCA↑,
TumCMig↓,
TumCI↓,
ROS↑, PL markedly elevated reactive oxygen species (ROS)
Slug↓, PL inhibited epithelial mesenchymal transition with profoundly decreased level of Slug, β-catenin, ZEB1 and N-Cadherin.
β-catenin/ZEB1↓,
Zeb1↓,
N-cadherin↓,
F-actin↓, decreased F-actin intensity in bladder cancer cells
GSH↓, Consistently, intracellular glutathione (GSH) levels were significantly reduced in T24 cells at 3 h of PL treatment
EMT↓, PL inhibited epithelial mesenchymal transition
CLDN1↓, The decline of Claudin-1 and ZO-1 upon PL treatment
ZO-1↓,

2953- PL,    Piperlongumine Acts as an Immunosuppressant by Exerting Prooxidative Effects in Human T Cells Resulting in Diminished TH17 but Enhanced Treg Differentiation
- in-vitro, Nor, NA
*ROS↑, PL increased the levels of intracellular reactive oxygen species and decreased glutathione in PBTs.
*GSTA1↓,
eff↝, promising agent for therapeutic immunosuppression by exerting prooxidative effects in human T cells resulting in a diminished TH17 but enhanced Treg cell differentiation.
*toxicity↓, In the present study, we found that PL was not toxic to primary human T cells, as opposed to the malignant T leukemia line Jurkat
ROS↑, Similar to primary human T cells, the ROS levels in Jurkat leukemia cells also increased significantly after PL treatment
*Hif1a↓, PL strongly inhibits the expression of HIF-1α in a dose-dependent manner starting already at a concentration of 1 μM PL

2954- PL,    The metabolites from traditional Chinese medicine targeting ferroptosis for cancer therapy
- Review, Var, NA
NRF2↑, PL significantly increased ROS levels and protein glutathionylation with a concomitant elevation in Nrf-2 expression
ROS↑, PL selectively destroyed hepatocellular carcinoma cells rather than normal hepatocytes via ROS–endoplasmic reticulum (ER)–MAPK–CHOP axis,
ER Stress↑,
MAPK↑,
CHOP↑,
selectivity↑, PL selectively killed human breast cancer MCF-7 cells instead of human MCF-10A breast epithelial cells
Keap1↝, PL directly interacted with Kelch-like ECH-associated protein-1 (Keap1), which resulted in Nrf-2-mediated HO-1 expression
HO-1↑,
Ferroptosis↑, pancreatic cancer cell death mainly via the induction of ROS-mediated 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?, Piperlongumine, a natural alkaloid isolated from the long pepper, selectively increases reactive oxygen species production and apoptotic cell death in cancer cells but not in normal cells.
*ROS∅,
other⇅, opposing effect of piperlongumine appears to be mediated by heme oxygenase-1 (HO-1)
HO-1↑, Piperlongumine upregulated HO-1 expression through the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2) signaling in both MCF-7 and MCF-10A cells.
*HO-1↑,
NRF2↑, piperlongumine-induced Nrf2 activation, HO-1 expression and cancer cell apoptosis are not dependent on the generation of reactive oxygen species.
Keap1↓, appears to inactivate Kelch-like ECH-associated protein-1 (Keap1)
cl‑PARP↑, Following piperlongumine treatment, cleaved PARP levels increased in time- (Fig. 1D) and dose-dependent
selectivity↑, These data clearly show that piperlongumine has a cancer cell-selective killing effect
GSH↓, piperlongumine can selectively decrease the level of reduced GSH and increase the level of oxidized GSSG, leading to ROS accumulation and subsequent apoptosis in cancer cells
GSSG↑, we observed piperlongumine-mediated depletion of GSH, a reduction in the GSH/GSSG ratio and accumulation of intracellular ROS in MCF-7 cells but not in MCF-10A cells

2956- PL,    Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis
- in-vitro, PC, NA
ROS↑, Piperlongumine (PL) is a natural product with cytotoxic properties restricted to cancer cells by significantly increasing intracellular reactive oxygen species (ROS) levels.
Ferroptosis↓, at least in part, the induction of ferroptosis,. requires the accumulation of ROS in an iron-dependent manner
GSH↓, Since we actually found that PL markedly depleted GSH (Fig. 1H), these results suggest that PL may inhibit GPX activity.
GPx↓,
cl‑PARP∅, PL did not induce the expression of typical apoptotic markers, such as cleaved PARP and cleaved caspase-3
cl‑Casp3∅,
eff↑, PL (15 uM) plus CN-A resulted in a further increase in the population of ROS-positive cells
eff↑, SSZ enhances the PL-induced ferroptotic death of pancreatic cancer cells.

2957- PL,    Piperlongumine Induces Cell Cycle Arrest via Reactive Oxygen Species Accumulation and IKKβ Suppression in Human Breast Cancer Cells
- in-vitro, BC, MCF-7
TumCP↓, We found that PL decreased MCF-7 cell proliferation and migration.
TumCMig↓,
TumCCA↑, PL induced G2/M phase cell cycle arrest.
ROS↑, PL induced intracellular reactive oxygen species (hydrogen peroxide) accumulation and glutathione depletion
H2O2↑,
GSH↓,
IKKα↓, PL-mediated inhibition of IKKβ expression decreased nuclear translocation of NF-κB p65.
NF-kB↓,
P21↑, PL significantly increased p21 mRNA levels.
eff↓, PL significantly decreased cellular GSH levels, while in cells pre-treated with NAC, the GSH levels were similar to those observed in control cells

2958- PL,    Natural product piperlongumine inhibits proliferation of oral squamous carcinoma cells by inducing ferroptosis and inhibiting intracellular antioxidant capacity
- in-vitro, Oral, HSC3
TumCP↓, proliferation rate of PL-treated OSCC cells were decreased in a dose- and time-dependent manner.
lipid-P↑, Lipid peroxidation (LPO) and intracellular reactive oxygen species (ROS) were accumulated after PL treatment.
ROS↑,
DNMT1↑, expression of DMT1 increased, and the expression of FTH1, SLC7A11 and GPX4 decreased.
FTH1↓,
GPx4↓,
eff↓, effect of PL on OSCC cells can be reversed by iron scavengers and antioxidants
GSH↓, PL can inhibit the synthesis of intracellular GSH to induce ferroptosis
Ferroptosis↑,
MDA↓, content of MDA decreased

2961- PL,    Piperlongumine inhibits esophageal squamous cell carcinoma in vitro and in vivo by triggering NRF2/ROS/TXNIP/NLRP3-dependent pyroptosis
- in-vitro, ESCC, KYSE-30
Pyro↑, PL significantly suppressed malignant behavior by promoting pyroptosis of ESCC cells by inhibiting proliferation, migration, invasion, and colony formation of KYSE-30 cells
TumCP↓,
TumCMig↓,
TumCI↓,
ASC↑, up-regulating expressions of ASC, Cleaved-caspase-1, NLRP3, and GSDMD, while inducing the generation of ROS.
cl‑Casp1↑,
NLRP3↑,
GSDMD↑,
ROS↑,
NRF2↓, PL inhibited the malignant behavior of ESCC cells in vitro and tumorigenesis of ESCC in vivo by inhibiting NRF2 and promoting ROS-TXNIP-NLRP3-mediated pyroptosis.
TXNIP↑,

2962- PL,    Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2‑Related Factor 2 (Nrf2) Activators as Potential Neuroprotective Agents
- in-vitro, Nor, PC12
*GSH↑, compounds 4 and 5 remarkably elevats GSH level and antioxidant enzymes activity (NQO1, Trx, and TrxR).
*NQO1↑,
*Trx↑,
*TrxR↑,
*NRF2↑, revealed that the total Nrf2 expression was slightly upregulated. 4 and 5, have been identified as potent Nrf2 activators with minimal cytotoxicity.
*NRF2⇅, Notably, the cytosolic Nrf2 decreased gradually (Figure 9, middle panel). Coincidently, the amount of Nrf2 in nuclei increased.
*eff↑, Induction of transcription of antioxidant genes via the Nrf2-dependent cytoprotective pathway requires translocation of Nrf2 from cytosol to nucleus.
*BioAv↑, PL could cross the BBB after oral administration
*ROS↓, The elevation of cellular endogenous antioxidant system prevents the accumulation of ROS and thus confers protection against oxidative insults to the cells.

2950- PL,    Overview of piperlongumine analogues and their therapeutic potential
- Review, Var, NA
AntiAg↑, PL has been shown to exert in vitro antiplatelet aggregation effect induced by agonists such as collagen, adenosine 50-diphosphate (ADP), arachidonic acid (AA) and thrombin.
neuroP↑, Neuroprotective activity of PL and its derivatives
Inflam↓, Anti-inflammatory activity of PL and its derivatives
NO↓, production of NO and PGE2 was significantly inhibited after the treatment of PL.
PGE2↓,
MMP3↓, PL also significantly suppressed the production of MMP-3 and MMP-13
MMP13↓,
TumCMig↓, PL inhibited the proliferation, induced the apoptosis and reduced the migration and invasion of RA FLS by activating the p38, JNK, NF-kB and STAT3 pathways
TumCI↓,
p38↑,
JNK↑,
NF-kB↑,
ROS↑, PL has been reported to selectively induce apoptotic by ROS accumulation in cancer cells via different molecular mechanisms.
Foxm1↓, PL inhibited proteasome including suppression of FOXM1
TrxR1↓, induction of ROS by directly inhibiting thioredoxin reductase 1 (TrxR1) activity
GSH↓, Wang et al. demonstrated that PL could inhibit both glutathione and thioredoxin and thus induce ROS elevation,
Trx↓,
cMyc↓, downregulation of c-Myc and LMP1 and the Caspase-3-dependent apoptosis of Burkitt lymphoma cells in vitro.
Casp3↑,
Bcl-2↓, PL could downregulate Bcl-2 and Mcl-1 and decrease the expression of STAT-3
Mcl-1↓,
STAT3↓, Bharadwaj et al. identified PL as a direct STAT3 inhibitor
AR↓, Golovine et al. demonstrated for the first time that PL rapidly reduced the androgen receptor protein level of prostate cancer cells
DNAdam↑, inducing DNA damage,

2966- PL,    A strategy to improve the solubility and bioavailability of the insoluble drug piperlongumine through albumin nanoparticles
- in-vitro, LiverDam, NA
*Half-Life↑, pharmacokinetic properties of PL-BSA-NPs were shown that PL-BSA-NPs could maintain a certain level of blood drug concentration for a long time, thus demonstrating the sustained release and increased bioavailability of PL.
*BioAv↑,
eff↑, antitumor activity of the PL-BSA-NPs and found that PL can significantly inhibit HepG2 cell proliferation, and that PL-BSA-NPs enhanced the inhibitory effect of PL on this proliferative effect.
ROS↑, t PL can destroy liver cancer cells by increasing ROS levels.

2968- PL,  Chit,    Preparation of piperlongumine-loaded chitosan nanoparticles for safe and efficient cancer therapy
- in-vitro, GC, AGS
eff↑, The PL-CSNPs showed efficient cytotoxicity against human gastric carcinoma (AGS) cells via dramatic increase of intracellular ROS leading to cell apoptosis
Dose↝, Chitosan was mixed with NaTPP at a 4 : 1 weight ratio.
ROS↑, n contrast, the cells treated with PL–CSNPs and free PL indicated a signicant increase in intracellular ROS (
BioAv↑, Chitosan has been intensively explored for biocompatible drug carriers due to high biodegradability and low toxicity.

2969- PL,    Piperlongumine induces autophagy by targeting p38 signaling
- in-vitro, OS, U2OS - in-vitro, Cerv, HeLa
p38↑, PL stimulates the activation of p38 protein kinase through ROS-induced stress response
ROS↑, PL for 4 h led to 6- to 11-fold increases of the ROS levels in the cells
GPx1∅, PL treatment only marginally reduced antioxidant enzyme, glutathione peroxidase 1 (GPX1) expression, and had no effect on SOD and catalase levels in U2OS/GFP-LC3
SOD∅,
Catalase∅,

2973- PL,    The Natural Alkaloid Piperlongumine Inhibits Metastatic Activity and Epithelial-to-Mesenchymal Transition of Triple-Negative Mammary Carcinoma Cells
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, 4T1
MMP2↓, Piperlongumine-treated MDA-MB-231 cells showed reduced motility/invasiveness, decreased MMP2 and MMP9 expression,
MMP9↓,
IL6↓, increased miR-200c expression, reduced IL-6 synthesis, decreased expression of ZEB1 and Slug, increased E-cadherin expression, and epithelial-like morphology.
E-cadherin↑,
ROS↑, ROS accumulated in piperlongumine-treated cells,
EMT↓, Piperlongumine Suppresses EMT
Zeb1↓, EMT-promoting ZEB1 and Slug transcription factors was significantly downregulated
Slug↓,
TumMeta↓, sub-cytotoxic dose of piperlongumine prevented metastasis in a mouse model of TNBC
selectivity↑, capacity to induce apoptosis in cancer cells while sparing normal cells
NA↑, Low dose piperlongumine also suppressed the expression of MMP2 and MMP9,
GSH↓, The resulting depletion of ROS-scavenging GSH would be expected to cause oxidative stress due to the accumulation of intracellular ROS

1951- PL,    Piperlongumine Analogs Promote A549 Cell Apoptosis through Enhancing ROS Generation
- in-vitro, Lung, A549
ROS↑, the ROS accumulation could disrupt the redox balance, induce lipid peroxidation, lead to the loss of MMP (Mitochondrial Membrane Potential), and ultimately result in cell cycle arrest and A549 cell line death.
lipid-P↑,
MMP↓,
TumCCA↑,
TrxR↓, PL analogs could induce in vitro cancer apoptosis through the inhibition of TrxR
eff↑, For example, curcumin [15] and PL [16], characterized with the Michael acceptor, could irreversibly inhibit thioredoxin reductase (TrxR), and the adduct triggers ROS generation.

1938- PL,    Piperlongumine regulates epigenetic modulation and alleviates psoriasis-like skin inflammation via inhibition of hyperproliferation and inflammation
- Study, PSA, NA - in-vivo, NA, NA
ROS↑, In this study, we demonstrated that piperlongumine (PPL) treatment effectively abrogated the hyperproliferation and differentiation of keratinocytes by inducing ROS-mediated late apoptosis with loss of mitochondrial membrane potential.
Apoptosis↑,
MMP↓,
TumCCA↑, the arrest of cell cycle was found at Sub-G1 phase as a result of DNA fragmentation.
DNAdam↑,
STAT3↓, inhibition of STAT3 and Akt signaling was observed
Akt↓,
PCNA↓, decrease in proliferative markers such as PCNA, ki67, and Cyclin D1 along with anti-apoptotic Bcl-2 protein expression
Ki-67↓,
cycD1↓,
Bcl-2↓,
K17↓, Keratin 17 is a critical regulator of keratinocyte differentiation, and it was found to be downregulated with PPL significantly
HDAC↓, PPL epigenetically inhibited histone-modifying enzymes, which include histone deacetylases (HDACs) of class I (HDAC1–4) and class II (HDAC6)
ROS↑, PPL at 5 and 10 µM concentration increased the reactive oxygen species (ROS) levels and a marked increase in oxidative stress were observed when combined with H2O2
*IL1β↓, Topical IMQ prominently induced the levels of pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α, IL-17, IL-22, and transforming growth factor (TGF)-β, while PPL significantly suppressed these levels
*IL6↓,
*TNF-α↓,
*IL17↓,
*IL22↓,

1939- PL,    Piperlongumine selectively kills hepatocellular carcinoma cells and preferentially inhibits their invasion via ROS-ER-MAPKs-CHOP
- in-vitro, HCC, HepG2 - in-vitro, HCC, HUH7 - in-vivo, NA, NA
TumCMig↓, PL specifically suppressed HCC cell migration/invasion via endoplasmic reticulum (ER)-MAPKs-CHOP signaling pathway
TumCI↓,
ER Stress↑, Piperlongumine induces ER stress-responses which preferentially suppresses HCC cell migration/invasion
selectivity↑, PL selectively killed HCC cells but not normal hepatocytes with an IC50 of 10-20 μM while PL at much lower concentrations only suppressed HCC cell migration/invasion
tumCV↓,
ROS↑, Piperlongumine induces ROS accumulation to exert its anti-cancer effects on HCC cells
GSH↓, Consistently, intracellular glutathione (GSH) levels were significantly reduced in HepG2 or Huh7 cells at 1 h of PL treatment
eff↓, Pre-treatment of NAC or GSH completely reversed PL-induced cell death in Huh7 cells (Fig. 3E) and HepG2 cells
Ca+2↑, concentration of cytoplasmic free Ca2+ was prominently increased at 3 h of PL treatment in a dose-dependent manner (0-20 μM)
MAPK↑, Piperlongumine activates MAPKs signaling pathways which preferentially suppress HCC migration
CHOP↑, These evidences demonstrated that PL activated ER-MAPKs-CHOP axis signaling pathways via ROS-dependent mechanisms.
Dose↝, Notably, PL at a much lower concentration (1.5 mg/kg) showed a comparable anticancer effect in HCC-bearing mice and increasing PL concentration did not significantly enhance its anticancer effects

1940- PL,    Piperlongumine Inhibits Migration of Glioblastoma Cells via Activation of ROS-Dependent p38 and JNK Signaling Pathways
- in-vitro, GBM, LN229 - in-vitro, GBM, U87MG
ROS↑, demonstrated that PL induced ROS accumulation in scratched LN229 cells.
GSH↓, reduced glutathione
p38↑, activated p38 and JNK, increased IκBα
JNK↑,
IKKα↑,
NF-kB↓, suppressed NFκB in LN229 cells after scratching
eff↓, All the biological effects of PL in scratched LN229 cells were completely abolished by the antioxidant N-acetyl-L-cysteine (NAC).

1941- PL,    Piperlongumine selectively kills cancer cells and increases cisplatin antitumor activity in head and neck cancer
- in-vitro, HNSCC, NA
selectivity↑, Piperlongumine killed HNC cells regardless of p53 mutational status but spared normal cells.
eff↑, Piperlongumine increased cisplatin-induced cytotoxicity in HNC cells in a synergistic manner in vitro and in vivo.
ROS↑, Piperlongumine selectively increases ROS accumulation in HNC cells
toxicity↑, PL markedly induced death in cancer cells, while the viability of normal cells was affected only minimally at the highest concentration (15 μM) tested
GSH↓, PL decreased GSH levels and increased GSSG levels in HNC cells (Figure 2 and Supplementary Figure S1); however, PL did not increase GSSG levels in normal HOK-1 cells
GSSG↑,
*GSSG∅, however, PL did not increase GSSG levels in normal HOK-1 cells
cl‑PARP↑, PL increased the levels of PARP and PUMA proteins regardless of p53 status
PUMA↑,
GSTP1/GSTπ↓, PL regulates ROS by targeting GSTP1, a direct negative regulator of JNK [22, 23], and thereby increases JNK phosphorylation
ChemoSen↑, Piperlongumine increases the cytotoxicity of cisplatin in HNC cells in vitro and in vivo

1942- PL,    Piperlongumine inhibits antioxidant enzymes, increases ROS levels, induces DNA damage and G2/M cell cycle arrest in breast cell lines
- in-vitro, BC, MCF-7
ROS↑, PLN increased ROS levels and expression of the SOD1 antioxidant enzyme
SOD1↑,
Trx1↓, PLN inhibited the expression of the antioxidant enzymes catalase, TRx1, and PRx2.
Catalase↓,
PrxII↓,
ROS↑, ability of PLN to inhibit antioxidant enzyme expression was associated with the oxidative stress response
GADD45A↑, upregulated the levels of GADD45A mRNA and p21 protein.
P21↑,
DNAdam↑, In response to elevated ROS levels and DNA damage induction, the cells were arrested at the G2/M phase
TumCCA↑, arrested at the G2/M phase

1943- PL,    Piperlongumine treatment inactivates peroxiredoxin 4, exacerbates endoplasmic reticulum stress, and preferentially kills high-grade glioma cells
- in-vitro, GBM, NA - in-vivo, NA, NA
selectivity↑, Piperlongumine treatment increased ROS levels and preferentially killed HGG cells with little effect in normal brain cells.
ROS↑,
selectivity↑, piperlongumine treatment in HGG cells, but not in normal NSCs, increased oxidative inactivation of peroxiredoxin 4 (PRDX4), an ROS-reducing enzyme that is overexpressed in HGGs
Prx4↓, Piperlongumine Inactivates PRDX4 in HGG Cells
*Prx4∅,
ER Stress↑, Moreover, piperlongumine exacerbated intracellular ER stress
CHOP↑, We found that piperlongumine treatment rapidly and substantially increased CHOP protein levels in all 4 HGG sphere cultures
UPR↑, As with CHOP, other UPR protein levels were also increased upon piperlongumine treatment

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↑, PL induces a lethal endoplasmic reticulum (ER) stress response in HCC cells
TrxR1↓, PL treatment reduces TrxR1 activity and tumor cell burden in vivo
ROS↑, and increasing intracellular ROS levels
eff↓, Interestingly, pretreatment with NAC, a specific ROS inhibitor, for 2 h apparently suppressed PL-induced increases in ROS levels
Bcl-2↓, PL treatment decreased the levels of the antiapoptotic proteins Bcl-2 and procaspase3 and increased the levels of the proapoptotic proteins Bax and cleaved caspase-3 in a dose-dependent manner.
proCasp3↓,
BAX↓,
cl‑Casp3↑,
TumCCA↑, PL Induces ROS-Dependent G2/M Cell Cycle Arrest in HCC Cells
p‑PERK↑, PL increased the expression of p-PERK and ATF4 in a dose-dependent manner.
ATF4↑,
TumCG↓, PL Inhibits HUH-7 Xenograft Tumor Growth Accompanied by Increased ROS Levels and Decreased Trxr1 Activity
lipid-P↑, PL treatment increased the levels of the product of lipid peroxidation (MDA) in tumor tissues ( Figure 6H ), suggesting increased ROS levels
selectivity↑, In normal cells, TrxR1 can protect against oxidant stress

1945- PL,  SANG,    The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer
- in-vitro, Lung, A549
toxicity∅, Additionally, the compounds and their combination did not exhibit a cytotoxic effect against normal cells.
Apoptosis↑, PL and SAN increased apoptosis and favored metastasis inhibition.
TumMeta↓,
ROS↑, PL and SAN in a 4:1 ratio indicates a synergistic effect and is associated with an increase in the level of reactive oxygen species (ROS).
TumCCA↑, Combination on aCell Cycle Phases Distribution

1946- PL,  PI,    Piperlonguminine and Piperine Analogues as TrxR Inhibitors that Promote ROS and Autophagy and Regulate p38 and Akt/mTOR Signaling
- in-vitro, Liver, NA
eff↑, Among these, compound 9m exerted the most potent antiproliferative activity against drug-resistant Bel-7402/5-FU human liver cancer 5-FU resistant cells (IC50 = 0.8 μM), which was approximately 10-fold lower than piperlongumine (IC50 = 8.4 μM).
toxicity↓, Further, 9m showed considerably lower cytotoxicity against LO2 human normal liver epithelial cells compared to Bel-7402/5-FU.
TrxR↓, Mechanistically, compound 9m inhibited thioredoxin reductase (TrxR) activity, increased ROS levels, reduced mitochondrial transmembrane potential (MTP
ROS↑,
MMP↓,
p38↑, Finally, 9m activated significantly the p38 signaling pathways and suppressed the Akt/mTOR signaling pathways.
Akt↓,
mTOR↓,

1947- PL,    Piperlongumine as a direct TrxR1 inhibitor with suppressive activity against gastric cancer
- in-vitro, GC, SGC-7901 - in-vitro, GC, NA
TrxR1↓, In vivo, PL treatment markedly reduces the TrxR1 activity and tumor cell burden
ROS↑, PL may interact with the thioredoxin reductase 1 (TrxR1), an important selenocysteine (Sec)-containing antioxidant enzyme, to induce reactive oxygen species (ROS)-mediated apoptosis in human gastric cancer cells
ER Stress↑, PL induces a lethal endoplasmic reticulum stress and mitochondrial dysfunction in human gastric cancer cells
mtDam↑,
selectivity↑, known to selectively kill tumor cells while sparing their normal counterparts. PL treatment did not cause a significant increase in ROS levels in normal GES-1 cells
NO↑, we found that nitric oxide was also induced by PL in gastric cancer cells
TumCCA↑, PL treatment significantly induced G2/M cell cycle arrest in human gastric cancer SGC-7901, BGC-823 and KATO III cells.
mt-ROS↑, mitochondrial ROS, were involved in the PL-induced cell death in gastric cancer cells.
Casp9↑, Notably, caspase-9 activity was significantly elevated after PL treatment in SGC-7901 cells
Bcl-2↓, PL treatment dose-dependently decreased the expression of antiapoptotic proteins Bcl-2 and Bcl-xL, but induced the cleavage of poly (ADP-ribose) polymerase (PARP)
Bcl-xL↓,
cl‑PARP↑,
eff↓, Pre-incubation with GSH attenuated these effects confirming their linkage to PL-induced oxidative stress
lipid-P↑, PL dose-dependently increased the level of lipid peroxidation product (MDA), a marker of ROS, in tumor tissues

1948- PL,  born,    Natural borneol serves as an adjuvant agent to promote the cellular uptake of piperlongumine for improving its antiglioma efficacy
- in-vitro, GBM, NA
selectivity↑, Piperlongumine (PL) can selectively inhibit the proliferation of various cancer cells by increasing reactive oxygen species (ROS) level to cause a redox imbalance in cancer cells rather than in normal cells.
ROS↑, combination of NB and PL significantly induced higher levels of ROS
BioAv↓, clinical application of PL is limited by its poor cellular uptake.
BioAv↑, NB obviously promoted the cellular uptake of PL with a 1.3-fold increase in the maximum peak concentration and an earlier peak time of 30 min in C6 glioma cells.
Apoptosis↑, increased apoptosis and enhanced G2/M cycle arrest of C6 glioma cells, compared to PL alone administration.
TumCCA↑,
eff↑, NB-enhanced antiglioma efficacy of PL without side effects was confirmed in tumor-bearing mice, which was attributed to the improved cellular uptake of PL.

1949- PL,    Design, synthesis, and biological evaluation of a novel indoleamine 2,3-dioxigenase 1 (IDO1) and thioredoxin reductase (TrxR) dual inhibitor
- in-vitro, CRC, HCT116 - in-vitro, Cerv, HeLa
TrxR↓, piperlongumine (PL) and its derivatives have been reported to be inhibitors of TrxR.
selectivity↑, selective killing effect between normal and cancer cells.
ROS↑, ZC0101 had the ability to promote cellular ROS accumulation
IDO1↓, because of 4-phenylimidazole

1950- PL,    Increased Expression of FosB through Reactive Oxygen Species Accumulation Functions as Pro-Apoptotic Protein in Piperlongumine Treated MCF7 Breast Cancer Cells
- in-vitro, BC, MCF-7 - in-vitro, Lung, A549
selectivity↑, Piperlongumine (PL), a natural alkaloid compound isolated from long pepper (Piper longum), can selectively kill cancer cells, but not normal cells,
ROS↑, by accumulation of reactive oxygen species (ROS)
SETBP1↓, PL downregulates SETDB1 expression
cl‑Casp9↑, enhanced caspase 9 dependent-PARP cleavage during PL-induced cell death.
eff↓, ROS inhibitor NAC (N-acetyl cysteine) recovered SETDB1 expression decreased by PL.
FOSB↑, Decreased SETDB1 expression induced transcriptional activity of FosB during PL treatment. PL treatment dramatically increased FosB promoter activity up to 9-fold

1952- PL,  5-FU,    Piperlongumine induces ROS accumulation to reverse resistance of 5-FU in human colorectal cancer via targeting TrxR
- in-vivo, CRC, HCT8
ROS↑, PL acted as a ROS inducer via binding and inhibiting TrxR (IC50 around 10.17 μM).
TrxR↓,
eff↑, enhanced the therapeutic effects of 5-FU through the dephosphorylation of Akt in BALB/c athymic nude mice bearing HCT-8/5-FU tumor xenografts.
p‑Akt↓, promoting inhibition of Akt phosphorylation,

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↑, Piperlongumine (PL), a natural electrophilic alkaloid bearing two α, β-unsaturated imides, is a promising anticancer molecule by targeting the stress response to reactive oxygen species (ROS).
selectivity↑, 15-fold selectivity toward A549 cells over normal WI-38 cells.
TrxR↓, selenoprotein thioredoxin reductase (TrxR) is one of the targets by which PL-CL promotes the ROS generation.
TumCCA↑, S-phase arrest
GSH?, PL-CL sharply decreased the GSH levels of A549 cells in a dose- and time-dependent fashion (Figure 5A) but barely changed the GSH levels of WI-38 cells
H2O2↑, significant accumulation of ROS (O2.- and H2O2)

2649- PL,    Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence
- Review, Var, NA
AntiCan↑, investigated for its anticancer activity in various cancer types, including hematological cancers, colorectal, gastric, lung, breast, prostate, and oral cancers, melanoma, and glioma
ROS↑, Its in vitro anticancer activity can be attributed to induction of ROS through increased glutathione disulfide levels, decreased glutathione levels
GSH↓,
TrxR↓, inhibition of thioredoxin reductase (TrxR), an enzyme which reduces thioredoxin, a redox protein that protects against oxidative stress
Trx↓,
Apoptosis↑, PPL-mediated ROS accumulation further leads to ROS-mediated apoptosis
TumCCA↑, G1 or G2/M cell cycle arrest
ER Stress↑, ER stress
DNAdam↑, oxidative DNA damage
ChemoSen↑, PPL was reported to sensitize head and neck, gastric, and liver cancers to cisplatin [18], oxaliplatin [19], and sorafenib [20], respectively
BioAv↓, Additionally, its poor aqueous solubility and bioavailability limit its therapeutic potential

2940- PL,    Piperlongumine Induces Reactive Oxygen Species (ROS)-dependent Downregulation of Specificity Protein Transcription Factors
- in-vitro, PC, PANC1 - in-vitro, Lung, A549 - in-vitro, Kidney, 786-O - in-vitro, BC, SkBr3
ROS↑, characterized as an inducer of reactive oxygen species (ROS)
TumCP↓, 5-15 μM piperlongumine inhibited cell proliferation and induced apoptosis and ROS,
Apoptosis↑,
eff↓, these responses were attenuated after cotreatment with the antioxidant glutathione
Sp1/3/4↓, Piperlongumine also downregulated expression of Sp1, Sp3, Sp4
cycD1↓, and several pro-oncogenic Sp-regulated genes including cyclin D1, survivin, cMyc, epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (cMet)
survivin↓,
cMyc↓,
EGFR↓,
cMET↓,

2941- PL,    Selective killing of cancer cells by a small molecule targeting the stress response to ROS
- in-vivo, BC, MDA-MB-231 - in-vitro, OS, U2OS - in-vitro, BC, MDA-MB-453
ROS↑, . Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death
Apoptosis↑,
selectivity↑, but it has little effect on either rapidly or slowly dividing primary normal cells
*ROS∅, In contrast, PL did not cause an increase in ROS levels in normal cells
GSH↓, lead to a decrease in GSH and an increase in GSSG levels in cancer cells
GSSG↑,
H2O2↑, we found that hydrogen peroxide and nitric oxide, but not superoxide anion, were among the ROS species induced by PL in cancer cells
NO↑,
Half-Life?, 0.8 hrs

2942- PL,    Piperlongumine increases sensitivity of colorectal cancer cells to radiation: Involvement of ROS production via dual inhibition of glutathione and thioredoxin systems
- in-vitro, CRC, CT26 - in-vitro, CRC, DLD1 - in-vivo, CRC, CT26
ROS↑, known to selectively kill tumor cells via perturbation of reactive oxygen species (ROS) homeostasis
GSH↓, PL induced excessive production of ROS due to depletion of glutathione and inhibition of thioredoxin reductase
TrxR↓,
RadioS↑, PL enhanced both the intrinsic and hypoxic radiosensitivity of tumor cells
DNAdam↑, inked to ROS-mediated increase of DNA damage, G2/M cell cycle arrest, and inhibition of cellular respiration
TumCCA↑,
mitResp↓,
GSTs↓, PL proved to perturb GSH system by inhibition of glutathione S-transferase (GST) that catalyzes the conjugation of GSH with its substrate
OS↑, delays tumor growth and improves the survival rate of tumor-bearing mice.

2943- PL,    Piperlongumine Inhibits Thioredoxin Reductase 1 by Targeting Selenocysteine Residues and Sensitizes Cancer Cells to Erastin
- in-vitro, CRC, HCT116 - in-vitro, Lung, A549 - in-vitro, BC, MCF-7
TrxR1?, known to inhibit the cytosolic thioredoxin reductase (TXNRD1 or TrxR1) and selectively kill cancer cells.
TumCD↑,
ROS↑, Piperlongumine Induces ROS-Dependent Cancer Cell Death but Not Ferroptosis
GSH↓, we found that piperlongumine decreased the cellular GSH contents
eff↑, Piperlongumine Enhances Erastin-Induced Cancer Cells Death

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↑, it is selectively toxic to cancer cells by generating reactive oxygen species (ROS)
selectivity↑,
tumCV↓, Cell viability, colony formation, cell cycle, apoptosis, and cellular ROS induction.
TumCCA↑,
Apoptosis↑,
ERK↑, activation of Erk and the suppression of the Akt/mTOR pathways through ROS induction were seen in cells treated with PL
Akt↓,
mTOR↓,
neuroP↑, neuroprotective, and anticancer properties
Bcl-2↓, induces the downregulation of Bcl2 expression and the activation of caspase-3, poly (ADP-ribose) polymerase (PARP), and JNK
Casp3↑,
PARP↑,
JNK↑,
*toxicity↓, several whole-animal models, and it is highly safe when used in vivo
eff↓, Pre-treatment with N-acetylcysteine (NAC; a selective ROS scavenger) significantly reduced PL-mediated ROS activation
TumW↓, tumor weight in the PL (10 mg/kg) treatment group significantly decreased when compared with that in the control group

2945- PL,    Piperlongumine induces ROS mediated cell death and synergizes paclitaxel in human intestinal cancer cells
- in-vitro, CRC, HCT116
ROS↑, Piperlongumine (PL) kills intestinal cancer cells by elevating ROS levels.
SMAD4↑, PL significantly up-regulates SMAD4 expression, leading to apoptosis in cancer cells.
ChemoSen↑, PL with Paclitaxel can be a better option for chemotherapy.
P53↑, Remarkably, P53, P21, BAX, and SMAD4 were significantly upregulated after PL treatment whereas; BCL2 and SURVIVIN were down-regulated.
P21↑,
BAX↑,
Bcl-2↓,
survivin↓,
TumCMig↓, Piperlongumine suppresses migration of cancer cell

2946- PL,    Piperlongumine, a potent anticancer phytotherapeutic: Perspectives on contemporary status and future possibilities as an anticancer agent
- Review, Var, NA
ROS↑, piperlongumine inhibits cancer growth by resulting in the accumulation of intracellular reactive oxygen species, decreasing glutathione and chromosomal damage, or modulating key regulatory proteins, including PI3K, AKT, mTOR, NF-kβ, STATs, and cycD
GSH↓, reduced glutathione (GSH) levels in mouse colon cancer cells
DNAdam↑,
ChemoSen↑, combined treatment with piperlongumine potentiates the anticancer activity of conventional chemotherapeutics and overcomes resistance to chemo- and radio- therapy
RadioS↑, piperlongumine treatment enhances ROS production via decreasing GSH levels and causing thioredoxin reductase inhibition
BioEnh↑, Moreover, the bioavailability is significantly improved after oral administration of piperlongumine
selectivity↑, It shows selectivity toward human cancer cells over normal cells and has minimal side effects
BioAv↓, ts low aqueous solubility affects its anti-cancer activity by limiting its bioavailability during oral administration
eff↑, encapsulation of piperlongumine in another biocompatible natural polymer, chitosan, has been found to result in pH-dependent piperlongumine release and to enhance cytotoxicity via efficient intracellular ROS accumulation against human gastric carcin
p‑Akt↓, Fig 2
mTOR↓,
GSK‐3β↓,
β-catenin/ZEB1↓,
HK2↓, iperlongumine treatment decreases cell proliferation, single-cell colony-formation ability, and HK2-mediated glycolysis in NSCLC cells via inhibiting the interaction between HK2 and voltage-dependent anion channel 1 (VDAC1)
Glycolysis↓,
Cyt‑c↑,
Casp9↑,
Casp3↑,
Casp7↑,
cl‑PARP↑,
TrxR↓, piperlongumine (4 or 12 mg/kg/day for 15 days) administration significantly inhibits increase in tumor weight and volume with less TrxR1 activity in SGC-7901 cell
ER Stress↑,
ATF4↝,
CHOP↑, activating the downstream ER-MAPK-C/EBP homologous protein (CHOP) signaling pathway
Prx4↑, piperlongumine kills high-grade glioma cells via oxidative inactivation of PRDX4 mediated ROS induction, thereby inducing intracellular ER stress
NF-kB↓, piperlongumine treatment (2.5–5 mg/ kg body weight) decreases the growth of lung tumors via inhibition of NF-κB
cycD1↓, decreases expression of cyclin D1, cyclin- dependent kinase (CDK)-4, CDK-6, p- retinoblastoma (p-Rb)
CDK4↓,
CDK6↓,
p‑RB1↓,
RAS↓, piperlongumine downregulates the expression of Ras protein
cMyc↓, inhibiting the activity of other related proteins, such as Akt/NF-κB, c-Myc, and cyclin D1 in DMH + DSS induced colon tumor cells
TumCCA↑, by arresting colon tumor cells in the G2/M phase of the cell cycle
selectivity↑, hows more selective cytotoxicity against human breast cancer MCF-7 cells than human breast epithelial MCF-10A cells
STAT3↓, thus inducing inhibition of the STAT3 signaling pathway in multiple myeloma cells
NRF2↑, Nrf2) activation has been found to mediate the upregulation of heme oxygenase-1 (HO-1) in piperlongumine treated MCF-7 and MCF-10A cells
HO-1↑,
PTEN↑, stimulates ROS accumulation; p53, p27, and PTEN overexpression
P-gp↓, P-gp, MDR1, MRP1, survivin, p-Akt, NF-κB, and Twist downregulation;
MDR1↓,
MRP1↓,
survivin↓,
Twist↓,
AP-1↓, iperlongumine significantly suppresses the expression of transcription factors, such as AP-1, MYC, NF-κB, SP1, STAT1, STAT3, STAT6, and YY1.
Sp1/3/4↓,
STAT1↓,
STAT6↓,
SOX4↑, increased expression of p21, SOX4, and XBP in B-ALL cells
XBP-1↑,
P21↑,
eff↑, combined use of piperlongumine with cisplatin enhances the sensitivity toward cisplatin by inhibiting Akt phosphorylation
Inflam↓, inflammation (COX-2, IL6); invasion and metastasis, such as ICAM-1, MMP-9, CXCR-4, VEGF;
COX2↓,
IL6↓,
MMP9↓,
TumMeta↓,
TumCI↓,
ICAM-1↓,
CXCR4↓,
VEGF↓,
angioG↓,
Half-Life↝, The analysis of the plasma of piperlongumine treated mice (50 mg/kg) after intraperitoneal administration, 1511.9 ng/ml, 418.2 ng/ml, and 41.9 ng/ml concentrations ofplasma piperlongumine were found at 30 minutes, 3 hours, and 24 hours, respecti
BioAv↑, Moreover, the bioavailability is significantly improved after oral administration of piperlongumine

2947- PL,    Piperlongumine: the amazing amide alkaloid from Piper in the treatment of breast cancer
- Review, Var, NA
TumCP↓, exhibits potent activity against various cancer cell proliferation
Apoptosis↑, Apoptosis, cell cycle arrest, increased ROS generation
TumCCA↑,
ROS↑,

2949- PL,    Piperlongumine selectively kills glioblastoma multiforme cells via reactive oxygen species accumulation dependent JNK and p38 activation
- in-vitro, GBM, LN229 - in-vitro, GBM, U87MG
selectivity↑, Piperlongumine (PL) selectively kills GBM cells but not normal astrocytes.
ROS↑, PL kills GBM cells via ROS accumulation
JNK↑, JNK and p38 activation contributes to PL’s cytotoxicity in GBM cells.
p38↑,
GSH↓, PL elevated ROS prominently and reduced glutathione levels in LN229 and U87 cells.
eff↓, Antioxidant N-acetyl-l-cysteine (NAC) completely reversed PL-induced ROS accumulation and prevented cell death in LN229 and U87 cells.


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 40

Results for Effect on Cancer/Diseased Cells:
Akt↓,3,   p‑Akt↓,2,   angioG↓,1,   AntiAg↑,1,   AntiCan↑,1,   AP-1↓,1,   Apoptosis↑,8,   AR↓,1,   ASC↑,1,   ATF4↑,1,   ATF4↝,1,   BAX↓,1,   BAX↑,1,   Bcl-2↓,6,   Bcl-xL↓,1,   BioAv↓,3,   BioAv↑,3,   BioEnh↑,1,   Ca+2↑,1,   cl‑Casp1↑,1,   Casp3↑,3,   cl‑Casp3↑,1,   cl‑Casp3∅,1,   proCasp3↓,1,   Casp7↑,1,   Casp9↑,2,   cl‑Casp9↑,1,   Catalase↓,1,   Catalase∅,1,   CDK4↓,1,   CDK6↓,1,   ChemoSen↑,4,   CHOP↑,4,   CLDN1↓,1,   cMET↓,1,   cMyc↓,3,   COX2↓,1,   CXCR4↓,1,   cycD1↓,3,   Cyt‑c↑,1,   DNAdam↑,6,   DNMT1↑,1,   Dose↝,2,   E-cadherin↑,1,   eff↓,10,   eff↑,12,   eff↝,1,   EGFR↓,1,   EMT↓,2,   ER Stress↑,7,   ERK↑,1,   F-actin↓,1,   Ferroptosis↓,1,   Ferroptosis↑,2,   FOSB↑,1,   Foxm1↓,1,   FTH1↓,1,   GADD45A↑,1,   Glycolysis↓,1,   GPx↓,1,   GPx1∅,1,   GPx4↓,1,   GSDMD↑,1,   GSH?,1,   GSH↓,16,   GSK‐3β↓,1,   GSSG↑,3,   GSTP1/GSTπ↓,1,   GSTs↓,1,   H2O2↑,3,   Half-Life?,1,   Half-Life↝,1,   HDAC↓,1,   HK2↓,1,   HO-1↑,3,   ICAM-1↓,1,   IDO1↓,1,   IKKα↓,1,   IKKα↑,1,   IL6↓,2,   Inflam↓,2,   JNK↑,4,   K17↓,1,   Keap1↓,1,   Keap1↝,1,   Ki-67↓,1,   lipid-P↑,4,   MAPK↑,2,   Mcl-1↓,1,   MDA↓,1,   MDR1↓,1,   mitResp↓,1,   MMP↓,3,   MMP13↓,1,   MMP2↓,1,   MMP3↓,1,   MMP9↓,2,   MRP1↓,1,   mtDam↑,1,   mTOR↓,3,   N-cadherin↓,1,   NA↑,1,   neuroP↑,2,   NF-kB↓,3,   NF-kB↑,1,   NLRP3↑,1,   NO↓,1,   NO↑,2,   NRF2↓,1,   NRF2↑,3,   OS↑,1,   other⇅,1,   P-gp↓,1,   P21↑,4,   p38↑,5,   P53↑,1,   PARP↑,1,   cl‑PARP↑,4,   cl‑PARP∅,1,   PCNA↓,1,   p‑PERK↑,1,   PGE2↓,1,   Prx4↓,1,   Prx4↑,1,   PrxII↓,1,   PTEN↑,1,   PUMA↑,1,   Pyro↑,1,   RadioS↑,2,   RAS↓,1,   p‑RB1↓,1,   ROS?,1,   ROS↑,40,   mt-ROS↑,1,   selectivity↑,18,   SETBP1↓,1,   Slug↓,2,   SMAD4↑,1,   SOD∅,1,   SOD1↑,1,   SOX4↑,1,   Sp1/3/4↓,2,   STAT1↓,1,   STAT3↓,3,   STAT6↓,1,   survivin↓,3,   toxicity↓,1,   toxicity↑,1,   toxicity∅,1,   Trx↓,2,   Trx1↓,1,   TrxR↓,8,   TrxR1?,1,   TrxR1↓,3,   TumCCA↑,15,   TumCD↑,1,   TumCG↓,1,   TumCI↓,5,   TumCMig↓,6,   TumCP↓,6,   tumCV↓,2,   TumMeta↓,3,   TumW↓,1,   Twist↓,1,   TXNIP↑,1,   UPR↑,1,   VEGF↓,1,   XBP-1↑,1,   Zeb1↓,2,   ZO-1↓,1,   β-catenin/ZEB1↓,2,  
Total Targets: 171

Results for Effect on Normal Cells:
BioAv↑,2,   eff↑,1,   GSH↑,1,   GSSG∅,1,   GSTA1↓,1,   Half-Life↑,1,   Hif1a↓,1,   HO-1↑,1,   IL17↓,1,   IL1β↓,1,   IL22↓,1,   IL6↓,1,   NQO1↑,1,   NRF2↑,1,   NRF2⇅,1,   Prx4∅,1,   ROS↓,1,   ROS↑,1,   ROS∅,2,   TNF-α↓,1,   toxicity↓,2,   Trx↑,1,   TrxR↑,1,  
Total Targets: 23

Scientific Paper Hit Count for: ROS, Reactive Oxygen Species
40 Piperlongumine
1 chitosan
1 Sanguinarine
1 Piperine
1 borneol
1 5-fluorouracil
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:134  Target#:275  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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