Database Query Results : Piperlongumine, ,

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)


Scientific Papers found: Click to Expand⟱
2964- PL,    Preformulation Studies on Piperlongumine
- Analysis, Nor, NA
"highlight2" >*BioAv↓, The solubility of piperlongumine in water was found to be approximately 26 μg/ml.
"highlight2" >*BioAv↑, Using 10% polysorbate 80 as a surfactant resulted in a 27 fold increase in solubility.
"highlight2" >*other↝, maximum stability around pH 4. It was estimated that it would take approximately 17 weeks for piperlongumine to degrade by 10% at 25°C, pH 4.
"highlight2" >*eff↓, piperlongumine showed marked photo-degradation upon exposure to an ultraviolet light source, especially in aqueous media.

2951- PL,  AF,    Synergistic Dual Targeting of Thioredoxin and Glutathione Systems Irrespective of p53 in Glioblastoma Stem Cells
- in-vitro, GBM, U87MG
"highlight2" >GSH↓, natural product piperlongumine (PPL) inhibit the GSH system.
"highlight2" >eff↑, subsequent efficacy of PLL in combination with Au within a nanomolar range in GSCs. Auranofin (Au), a known TrxR1 inhibitor
"highlight2" >GSTP1/GSTπ↓, PPL is a natural alkaloid found in the plant Piper longum Linn that directly inhibits GSTP-1 and exhibits anti-cancer properties

2952- PL,    Piperlongumine suppresses bladder cancer invasion via inhibiting epithelial mesenchymal transition and F-actin reorganization
- in-vitro, Bladder, T24/HTB-9 - in-vivo, Bladder, NA
"highlight2" >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
"highlight2" >TumCCA↑,
"highlight2" >TumCMig↓,
"highlight2" >TumCI↓,
"highlight2" >ROS↑, PL markedly elevated reactive oxygen species (ROS)
"highlight2" >Slug↓, PL inhibited epithelial mesenchymal transition with profoundly decreased level of Slug, β-catenin, ZEB1 and N-Cadherin.
"highlight2" >β-catenin/ZEB1↓,
"highlight2" >Zeb1↓,
"highlight2" >N-cadherin↓,
"highlight2" >F-actin↓, decreased F-actin intensity in bladder cancer cells
"highlight2" >GSH↓, Consistently, intracellular glutathione (GSH) levels were significantly reduced in T24 cells at 3 h of PL treatment
"highlight2" >EMT↓, PL inhibited epithelial mesenchymal transition
"highlight2" >CLDN1↓, The decline of Claudin-1 and ZO-1 upon PL treatment
"highlight2" >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
"highlight2" >*ROS↑, PL increased the levels of intracellular reactive oxygen species and decreased glutathione in PBTs.
"highlight2" >*GSTA1↓,
"highlight2" >eff↝, promising agent for therapeutic immunosuppression by exerting prooxidative effects in human T cells resulting in a diminished TH17 but enhanced Treg cell differentiation.
"highlight2" >*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
"highlight2" >ROS↑, Similar to primary human T cells, the ROS levels in Jurkat leukemia cells also increased significantly after PL treatment
"highlight2" >*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
"highlight2" >NRF2↑, PL significantly increased ROS levels and protein glutathionylation with a concomitant elevation in Nrf-2 expression
"highlight2" >ROS↑, PL selectively destroyed hepatocellular carcinoma cells rather than normal hepatocytes via ROS–endoplasmic reticulum (ER)–MAPK–CHOP axis,
"highlight2" >ER Stress↑,
"highlight2" >MAPK↑,
"highlight2" >CHOP↑,
"highlight2" >selectivity↑, PL selectively killed human breast cancer MCF-7 cells instead of human MCF-10A breast epithelial cells
"highlight2" >Keap1↝, PL directly interacted with Kelch-like ECH-associated protein-1 (Keap1), which resulted in Nrf-2-mediated HO-1 expression
"highlight2" >HO-1↑,
"highlight2" >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
"highlight2" >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.
"highlight2" >*ROS∅,
"highlight2" >other⇅, opposing effect of piperlongumine appears to be mediated by heme oxygenase-1 (HO-1)
"highlight2" >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.
"highlight2" >*HO-1↑,
"highlight2" >NRF2↑, piperlongumine-induced Nrf2 activation, HO-1 expression and cancer cell apoptosis are not dependent on the generation of reactive oxygen species.
"highlight2" >Keap1↓, appears to inactivate Kelch-like ECH-associated protein-1 (Keap1)
"highlight2" >cl‑PARP↑, Following piperlongumine treatment, cleaved PARP levels increased in time- (Fig. 1D) and dose-dependent
"highlight2" >selectivity↑, These data clearly show that piperlongumine has a cancer cell-selective killing effect
"highlight2" >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
"highlight2" >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
"highlight2" >ROS↑, Piperlongumine (PL) is a natural product with cytotoxic properties restricted to cancer cells by significantly increasing intracellular reactive oxygen species (ROS) levels.
"highlight2" >Ferroptosis↓, at least in part, the induction of ferroptosis,. requires the accumulation of ROS in an iron-dependent manner
"highlight2" >GSH↓, Since we actually found that PL markedly depleted GSH (Fig. 1H), these results suggest that PL may inhibit GPX activity.
"highlight2" >GPx↓,
"highlight2" >cl‑PARP∅, PL did not induce the expression of typical apoptotic markers, such as cleaved PARP and cleaved caspase-3
"highlight2" >cl‑Casp3∅,
"highlight2" >eff↑, PL (15 uM) plus CN-A resulted in a further increase in the population of ROS-positive cells
"highlight2" >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
"highlight2" >TumCP↓, We found that PL decreased MCF-7 cell proliferation and migration.
"highlight2" >TumCMig↓,
"highlight2" >TumCCA↑, PL induced G2/M phase cell cycle arrest.
"highlight2" >ROS↑, PL induced intracellular reactive oxygen species (hydrogen peroxide) accumulation and glutathione depletion
"highlight2" >H2O2↑,
"highlight2" >GSH↓,
"highlight2" >IKKα↓, PL-mediated inhibition of IKKβ expression decreased nuclear translocation of NF-κB p65.
"highlight2" >NF-kB↓,
"highlight2" >P21↑, PL significantly increased p21 mRNA levels.
"highlight2" >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
"highlight2" >TumCP↓, proliferation rate of PL-treated OSCC cells were decreased in a dose- and time-dependent manner.
"highlight2" >lipid-P↑, Lipid peroxidation (LPO) and intracellular reactive oxygen species (ROS) were accumulated after PL treatment.
"highlight2" >ROS↑,
"highlight2" >DNMT1↑, expression of DMT1 increased, and the expression of FTH1, SLC7A11 and GPX4 decreased.
"highlight2" >FTH1↓,
"highlight2" >GPx4↓,
"highlight2" >eff↓, effect of PL on OSCC cells can be reversed by iron scavengers and antioxidants
"highlight2" >GSH↓, PL can inhibit the synthesis of intracellular GSH to induce ferroptosis
"highlight2" >Ferroptosis↑,
"highlight2" >MDA↓, content of MDA decreased

2959- PL,    Piperlongumine mitigates LPS-induced inflammation and lung injury via targeting MD2/TLR4
- in-vivo, Nor, NA
"highlight2" >*Inflam↓, PL significantly inhibited LPS-induced inflammatory cytokines, chemokines, and type I IFNs genetic expression, along with the inhibition of TAK1 and TBK1 pathway.

2960- PL,    Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators as Potential Neuroprotective Agents
- Analysis, Nor, NA
"highlight2" >NRF2↑, Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators as Potential Neuroprotective Agents Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2-Related Factor
"highlight2" >neuroP↑,

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
"highlight2" >Pyro↑, PL significantly suppressed malignant behavior by promoting pyroptosis of ESCC cells by inhibiting proliferation, migration, invasion, and colony formation of KYSE-30 cells
"highlight2" >TumCP↓,
"highlight2" >TumCMig↓,
"highlight2" >TumCI↓,
"highlight2" >ASC↑, up-regulating expressions of ASC, Cleaved-caspase-1, NLRP3, and GSDMD, while inducing the generation of ROS.
"highlight2" >cl‑Casp1↑,
"highlight2" >NLRP3↑,
"highlight2" >GSDMD↑,
"highlight2" >ROS↑,
"highlight2" >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.
"highlight2" >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
"highlight2" >*GSH↑, compounds 4 and 5 remarkably elevats GSH level and antioxidant enzymes activity (NQO1, Trx, and TrxR).
"highlight2" >*NQO1↑,
"highlight2" >*Trx↑,
"highlight2" >*TrxR↑,
"highlight2" >*NRF2↑, revealed that the total Nrf2 expression was slightly upregulated. 4 and 5, have been identified as potent Nrf2 activators with minimal cytotoxicity.
"highlight2" >*NRF2⇅, Notably, the cytosolic Nrf2 decreased gradually (Figure 9, middle panel). Coincidently, the amount of Nrf2 in nuclei increased.
"highlight2" >*eff↑, Induction of transcription of antioxidant genes via the Nrf2-dependent cytoprotective pathway requires translocation of Nrf2 from cytosol to nucleus.
"highlight2" >*BioAv↑, PL could cross the BBB after oral administration
"highlight2" >*ROS↓, The elevation of cellular endogenous antioxidant system prevents the accumulation of ROS and thus confers protection against oxidative insults to the cells.

2963- PL,    Piperlongumine activates Sirtuin1 and improves cognitive function in a murine model of Alzheimer’s disease
- in-vitro, AD, HEK293
"highlight2" >*SIRT1↑, Piperlongumine (PL) activates the deacetylase ability of Sirt1 in vitro.
"highlight2" >*cognitive↑, PL improves cognitive deficits in APP/PS1 mice.
"highlight2" >*Aβ↓, PL reduces amyloid deposition and neuro-inflammation in the brain of APP/PS1 mice.
"highlight2" >*Inflam↓,
"highlight2" >*neuroP↑,
"highlight2" >memory↑, Sirt1 has been shown to modulate synaptic plasticity and memory formation
"highlight2" >Dose↓, PL induced Sirt1 deacetylase activity at a relatively low concentration, i.e. 1.5 uM, compared to the resveratrol treatment.
"highlight2" >NAD↑, PL treatment at doses of 0.5 and 4 μM significantly increased the level of NAD + . These results indicate that PL might activate Sirt1, subsequently changing the NAD + /NADH ratio

2950- PL,    Overview of piperlongumine analogues and their therapeutic potential
- Review, Var, NA
"highlight2" >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.
"highlight2" >neuroP↑, Neuroprotective activity of PL and its derivatives
"highlight2" >Inflam↓, Anti-inflammatory activity of PL and its derivatives
"highlight2" >NO↓, production of NO and PGE2 was significantly inhibited after the treatment of PL.
"highlight2" >PGE2↓,
"highlight2" >MMP3↓, PL also significantly suppressed the production of MMP-3 and MMP-13
"highlight2" >MMP13↓,
"highlight2" >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
"highlight2" >TumCI↓,
"highlight2" >p38↑,
"highlight2" >JNK↑,
"highlight2" >NF-kB↑,
"highlight2" >ROS↑, PL has been reported to selectively induce apoptotic by ROS accumulation in cancer cells via different molecular mechanisms.
"highlight2" >FOXM1↓, PL inhibited proteasome including suppression of FOXM1
"highlight2" >TrxR1↓, induction of ROS by directly inhibiting thioredoxin reductase 1 (TrxR1) activity
"highlight2" >GSH↓, Wang et al. demonstrated that PL could inhibit both glutathione and thioredoxin and thus induce ROS elevation,
"highlight2" >Trx↓,
"highlight2" >cMyc↓, downregulation of c-Myc and LMP1 and the Caspase-3-dependent apoptosis of Burkitt lymphoma cells in vitro.
"highlight2" >Casp3↑,
"highlight2" >Bcl-2↓, PL could downregulate Bcl-2 and Mcl-1 and decrease the expression of STAT-3
"highlight2" >Mcl-1↓,
"highlight2" >STAT3↓, Bharadwaj et al. identified PL as a direct STAT3 inhibitor
"highlight2" >AR↓, Golovine et al. demonstrated for the first time that PL rapidly reduced the androgen receptor protein level of prostate cancer cells
"highlight2" >DNAdam↑, inducing DNA damage,

2965- PL,  docx,    Piperlongumine for enhancing oral bioavailability and cytotoxicity of docetaxel in triple negative breast cancer
- Analysis, Var, NA
"highlight2" >BioEnh↑, Piperlongumine could be a potential candidate in overcoming the obstacles associated with oral docetaxel delivery with synergistic anticancer activity.
"highlight2" >eff↑, The IC50 value of DTX was reduced 3-5 times and combination

2966- PL,    A strategy to improve the solubility and bioavailability of the insoluble drug piperlongumine through albumin nanoparticles
- in-vitro, LiverDam, NA
"highlight2" >*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.
"highlight2" >*BioAv↑,
"highlight2" >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.
"highlight2" >ROS↑, t PL can destroy liver cancer cells by increasing ROS levels.

2967- PL,    Piperlongumine and its derivatives against cancer: A recent update and future prospective
- Review, Var, NA
"highlight2" >BioAv↓, it has poor intrinsic properties (low aqueous solubility, poor bioavailability, etc.).
"highlight2" >BioAv↑, attachment of ligustrazine and 4-hydroxycoumarin heterocyclic rings in place of phenyl rings, and attachment of heterocyclic rings like indole at the C7-C8 olefin position in native PL can help to improve anticancer activity, aqueous solubility, cell

2968- PL,  Chit,    Preparation of piperlongumine-loaded chitosan nanoparticles for safe and efficient cancer therapy
- in-vitro, GC, AGS
"highlight2" >eff↑, The PL-CSNPs showed efficient cytotoxicity against human gastric carcinoma (AGS) cells via dramatic increase of intracellular ROS leading to cell apoptosis
"highlight2" >Dose↝, Chitosan was mixed with NaTPP at a 4 : 1 weight ratio.
"highlight2" >ROS↑, n contrast, the cells treated with PL–CSNPs and free PL indicated a signicant increase in intracellular ROS (
"highlight2" >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
"highlight2" >p38↑, PL stimulates the activation of p38 protein kinase through ROS-induced stress response
"highlight2" >ROS↑, PL for 4 h led to 6- to 11-fold increases of the ROS levels in the cells
"highlight2" >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
"highlight2" >SOD∅,
"highlight2" >Catalase∅,

2970- PL,    Piperlongumine induces apoptosis and autophagy in leukemic cells through targeting the PI3K/Akt/mTOR and p38 signaling pathways
- in-vitro, AML, NA
"highlight2" >AntiAg↑, antiplatelet aggregation
"highlight2" >TumCG↓, cell growth of leukemic cells was completely inhibited following treatment with piperlongumine, and marked apoptosis was also induced
"highlight2" >Apoptosis↑,
"highlight2" >PI3K↓, Phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling was suppressed by treatment with piperlongumine, while p38 signaling and caspase-3 activity were induced by treatment with piperlongumine.
"highlight2" >Akt↓,
"highlight2" >mTOR↓,
"highlight2" >p38↑,
"highlight2" >Casp3↑,

2971- PL,    Piperlongumine attenuates IL-1β-induced inflammatory response in chondrocytes
- NA, OS, NA
"highlight2" >*NO↓, PLM significantly inhibited the production of NO and PGE2, iNOS and COX-2 expression, as well as suppressed the production of MMP-3 and MMP-13 in IL-1β-stimulated human OA chondrocytes
"highlight2" >*PGE2↓,
"highlight2" >*iNOS↓,
"highlight2" >*COX2↓,
"highlight2" >*MMP3↑,
"highlight2" >*MMP13↓,
"highlight2" >*Inflam↓, PLM may serve as a potential anti-inflammatory agent in the treatment of OA

2972- PL,    Piperlongumine Is an NLRP3 Inhibitor With Anti-inflammatory Activity
- in-vitro, AML, THP1
"highlight2" >NLRP3↓, PL is a natural inhibitor of Nod-like receptor family pyrin domain-containing protein-3 (NLRP3) inflammasome,
"highlight2" >IL1β↓, We further observed that PL inhibited IL-1β secretion, LDH release, and caspase-1 cleavage when macrophages were treated with other NLRP3 agonists, including ATP and MSU
"highlight2" >LDH↓,
"highlight2" >cl‑Casp1↓,
"highlight2" >Inflam↓, Piperlongumine Suppresses NLRP3-Dependent Inflammation in vivo

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
"highlight2" >MMP2↓, Piperlongumine-treated MDA-MB-231 cells showed reduced motility/invasiveness, decreased MMP2 and MMP9 expression,
"highlight2" >MMP9↓,
"highlight2" >IL6↓, increased miR-200c expression, reduced IL-6 synthesis, decreased expression of ZEB1 and Slug, increased E-cadherin expression, and epithelial-like morphology.
"highlight2" >E-cadherin↑,
"highlight2" >ROS↑, ROS accumulated in piperlongumine-treated cells,
"highlight2" >EMT↓, Piperlongumine Suppresses EMT
"highlight2" >Zeb1↓, EMT-promoting ZEB1 and Slug transcription factors was significantly downregulated
"highlight2" >Slug↓,
"highlight2" >TumMeta↓, sub-cytotoxic dose of piperlongumine prevented metastasis in a mouse model of TNBC
"highlight2" >selectivity↑, capacity to induce apoptosis in cancer cells while sparing normal cells
"highlight2" >MMP2↓, Low dose piperlongumine also suppressed the expression of MMP2 and MMP9,
"highlight2" >GSH↓, The resulting depletion of ROS-scavenging GSH would be expected to cause oxidative stress due to the accumulation of intracellular ROS

2995- PL,    Piperlongumine overcomes osimertinib resistance via governing ubiquitination-modulated Sp1 turnover
- in-vitro, Lung, H1975 - in-vitro, Lung, PC9 - in-vivo, NA, NA
"highlight2" >Sp1/3/4↓, piperlongumine could enhance the interaction between E3 ligase RNF4 and Sp1, inhibit the phosphorylation of Sp1 at Thr739, facilitate the ubiquitination and degradation of Sp1, lead to c-Met destabilization, and trigger intrinsic apoptosis in resista
"highlight2" >cMET↓,
"highlight2" >Apoptosis↑,
"highlight2" >Cyt‑c↑, piperlongumine promoted the release of cytochrome c from the mitochondria to the cytoplasm while facilitating the translocation of Bcl-2-associated X protein (Bax) to the mitochondria
"highlight2" >p‑ERK↓, dose-dependent decrease in the protein levels of c-Met, phosphorylated ERK1/2 (p-ERK1/2), and p-Akt
"highlight2" >p‑Akt↓,
"highlight2" >TumCG↓, These data suggest that piperlongumine exhibits good tolerability and effectively inhibits tumor growth of osimertinib-resistant cells in vivo.

2996- PL,    Application of longinamide in inhibiting the activation of NLRP3 inflammasome
- NA, AD, NA - NA, Park, NA
"highlight2" >*NLRP3↓, piperlongumine can inhibit the activation of NLRP3 inflammasome induced by nigericin in mouse macrophages and human mononuclear macrophages,

2999- PL,    Piperlongumine alleviates corneal allograft rejection via suppressing angiogenesis and inflammation
- in-vivo, Nor, HUVECs
"highlight2" >*Inflam↓, In vivo, PL treatment effectively attenuated corneal allograft rejection, paralleled by coincident suppression of neovascularization and alleviation of inflammatory response.
"highlight2" >*angioG↓, PL distinctively inhibited hypoxia-induced angiogenic processes in HUVECs
"highlight2" >*Hif1a↓, Two key players in hypoxia-induced angiogenesis, HIF-1α and VEGF-A were significantly suppressed by PL treatment.
"highlight2" >*VEGF↓,
"highlight2" >*ICAM-1↓, pronounced reduction in ICAM-1, VCAM-1, CCL2, and CXCL5 expression.
"highlight2" >*VCAM-1↓,
"highlight2" >*neuroP↑, including anti-tumoral, anti-depressant, anti-diabetic, anti-atherosclerotic and neuroprotective properties

3000- PL,    Biological and physical approaches on the role of piplartine (piperlongumine) in cancer
- in-vitro, Nor, HUVECs - in-vitro, Laryn, HEp2
"highlight2" >Inflam↓, anti-inflammatory and antitumor activity.
"highlight2" >AntiTum↑,
"highlight2" >*α-tubulin↓, PL inhibits α-tubulin expression
"highlight2" >selectivity↑, PL appeared to have no effect on the migration and invasion ability of normal or neoplastic cells
"highlight2" >HIF2a↓, Other groups have expanded the knowledge of the biological properties of PL and suggested, inter alia, that PL inhibits hypoxia inducible factor-2 (HIF-2) transcription
"highlight2" >MCP1↓, reduced the MCP-1 levels,

1951- PL,    Piperlongumine Analogs Promote A549 Cell Apoptosis through Enhancing ROS Generation
- in-vitro, Lung, A549
"highlight2" >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.
"highlight2" >lipid-P↑,
"highlight2" >MMP↓,
"highlight2" >TumCCA↑,
"highlight2" >TrxR↓, PL analogs could induce in vitro cancer apoptosis through the inhibition of TrxR
"highlight2" >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
"highlight2" >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.
"highlight2" >Apoptosis↑,
"highlight2" >MMP↓,
"highlight2" >TumCCA↑, the arrest of cell cycle was found at Sub-G1 phase as a result of DNA fragmentation.
"highlight2" >DNAdam↑,
"highlight2" >STAT3↓, inhibition of STAT3 and Akt signaling was observed
"highlight2" >Akt↓,
"highlight2" >PCNA↓, decrease in proliferative markers such as PCNA, ki67, and Cyclin D1 along with anti-apoptotic Bcl-2 protein expression
"highlight2" >Ki-67↓,
"highlight2" >cycD1/CCND1↓,
"highlight2" >Bcl-2↓,
"highlight2" >K17↓, Keratin 17 is a critical regulator of keratinocyte differentiation, and it was found to be downregulated with PPL significantly
"highlight2" >HDAC↓, PPL epigenetically inhibited histone-modifying enzymes, which include histone deacetylases (HDACs) of class I (HDAC1–4) and class II (HDAC6)
"highlight2" >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
"highlight2" >*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
"highlight2" >*IL6↓,
"highlight2" >*TNF-α↓,
"highlight2" >*IL17↓,
"highlight2" >*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
"highlight2" >TumCMig↓, PL specifically suppressed HCC cell migration/invasion via endoplasmic reticulum (ER)-MAPKs-CHOP signaling pathway
"highlight2" >TumCI↓,
"highlight2" >ER Stress↑, Piperlongumine induces ER stress-responses which preferentially suppresses HCC cell migration/invasion
"highlight2" >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
"highlight2" >tumCV↓,
"highlight2" >ROS↑, Piperlongumine induces ROS accumulation to exert its anti-cancer effects on HCC cells
"highlight2" >GSH↓, Consistently, intracellular glutathione (GSH) levels were significantly reduced in HepG2 or Huh7 cells at 1 h of PL treatment
"highlight2" >eff↓, Pre-treatment of NAC or GSH completely reversed PL-induced cell death in Huh7 cells (Fig. 3E) and HepG2 cells
"highlight2" >Ca+2↑, concentration of cytoplasmic free Ca2+ was prominently increased at 3 h of PL treatment in a dose-dependent manner (0-20 μM)
"highlight2" >MAPK↑, Piperlongumine activates MAPKs signaling pathways which preferentially suppress HCC migration
"highlight2" >CHOP↑, These evidences demonstrated that PL activated ER-MAPKs-CHOP axis signaling pathways via ROS-dependent mechanisms.
"highlight2" >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
"highlight2" >ROS↑, demonstrated that PL induced ROS accumulation in scratched LN229 cells.
"highlight2" >GSH↓, reduced glutathione
"highlight2" >p38↑, activated p38 and JNK, increased IκBα
"highlight2" >JNK↑,
"highlight2" >IKKα↑,
"highlight2" >NF-kB↓, suppressed NFκB in LN229 cells after scratching
"highlight2" >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
"highlight2" >selectivity↑, Piperlongumine killed HNC cells regardless of p53 mutational status but spared normal cells.
"highlight2" >eff↑, Piperlongumine increased cisplatin-induced cytotoxicity in HNC cells in a synergistic manner in vitro and in vivo.
"highlight2" >ROS↑, Piperlongumine selectively increases ROS accumulation in HNC cells
"highlight2" >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
"highlight2" >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
"highlight2" >GSSG↑,
"highlight2" >*GSSG∅, however, PL did not increase GSSG levels in normal HOK-1 cells
"highlight2" >cl‑PARP↑, PL increased the levels of PARP and PUMA proteins regardless of p53 status
"highlight2" >PUMA↑,
"highlight2" >GSTP1/GSTπ↓, PL regulates ROS by targeting GSTP1, a direct negative regulator of JNK [22, 23], and thereby increases JNK phosphorylation
"highlight2" >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
"highlight2" >ROS↑, PLN increased ROS levels and expression of the SOD1 antioxidant enzyme
"highlight2" >SOD1↑,
"highlight2" >Trx1↓, PLN inhibited the expression of the antioxidant enzymes catalase, TRx1, and PRx2.
"highlight2" >Catalase↓,
"highlight2" >PrxII↓,
"highlight2" >ROS↑, ability of PLN to inhibit antioxidant enzyme expression was associated with the oxidative stress response
"highlight2" >GADD45A↑, upregulated the levels of GADD45A mRNA and p21 protein.
"highlight2" >P21↑,
"highlight2" >DNAdam↑, In response to elevated ROS levels and DNA damage induction, the cells were arrested at the G2/M phase
"highlight2" >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
"highlight2" >selectivity↑, Piperlongumine treatment increased ROS levels and preferentially killed HGG cells with little effect in normal brain cells.
"highlight2" >ROS↑,
"highlight2" >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
"highlight2" >Prx4↓, Piperlongumine Inactivates PRDX4 in HGG Cells
"highlight2" >*Prx4∅,
"highlight2" >ER Stress↑, Moreover, piperlongumine exacerbated intracellular ER stress
"highlight2" >CHOP↑, We found that piperlongumine treatment rapidly and substantially increased CHOP protein levels in all 4 HGG sphere cultures
"highlight2" >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
"highlight2" >ER Stress↑, PL induces a lethal endoplasmic reticulum (ER) stress response in HCC cells
"highlight2" >TrxR1↓, PL treatment reduces TrxR1 activity and tumor cell burden in vivo
"highlight2" >ROS↑, and increasing intracellular ROS levels
"highlight2" >eff↓, Interestingly, pretreatment with NAC, a specific ROS inhibitor, for 2 h apparently suppressed PL-induced increases in ROS levels
"highlight2" >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.
"highlight2" >proCasp3↓,
"highlight2" >BAX↓,
"highlight2" >cl‑Casp3↑,
"highlight2" >TumCCA↑, PL Induces ROS-Dependent G2/M Cell Cycle Arrest in HCC Cells
"highlight2" >p‑PERK↑, PL increased the expression of p-PERK and ATF4 in a dose-dependent manner.
"highlight2" >ATF4↑,
"highlight2" >TumCG↓, PL Inhibits HUH-7 Xenograft Tumor Growth Accompanied by Increased ROS Levels and Decreased Trxr1 Activity
"highlight2" >lipid-P↑, PL treatment increased the levels of the product of lipid peroxidation (MDA) in tumor tissues ( Figure 6H ), suggesting increased ROS levels
"highlight2" >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
"highlight2" >toxicity∅, Additionally, the compounds and their combination did not exhibit a cytotoxic effect against normal cells.
"highlight2" >Apoptosis↑, PL and SAN increased apoptosis and favored metastasis inhibition.
"highlight2" >TumMeta↓,
"highlight2" >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).
"highlight2" >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
"highlight2" >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).
"highlight2" >toxicity↓, Further, 9m showed considerably lower cytotoxicity against LO2 human normal liver epithelial cells compared to Bel-7402/5-FU.
"highlight2" >TrxR↓, Mechanistically, compound 9m inhibited thioredoxin reductase (TrxR) activity, increased ROS levels, reduced mitochondrial transmembrane potential (MTP
"highlight2" >ROS↑,
"highlight2" >MMP↓,
"highlight2" >p38↑, Finally, 9m activated significantly the p38 signaling pathways and suppressed the Akt/mTOR signaling pathways.
"highlight2" >Akt↓,
"highlight2" >mTOR↓,

1947- PL,    Piperlongumine as a direct TrxR1 inhibitor with suppressive activity against gastric cancer
- in-vitro, GC, SGC-7901 - in-vitro, GC, NA
"highlight2" >TrxR1↓, In vivo, PL treatment markedly reduces the TrxR1 activity and tumor cell burden
"highlight2" >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
"highlight2" >ER Stress↑, PL induces a lethal endoplasmic reticulum stress and mitochondrial dysfunction in human gastric cancer cells
"highlight2" >mtDam↑,
"highlight2" >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
"highlight2" >NO↑, we found that nitric oxide was also induced by PL in gastric cancer cells
"highlight2" >TumCCA↑, PL treatment significantly induced G2/M cell cycle arrest in human gastric cancer SGC-7901, BGC-823 and KATO III cells.
"highlight2" >mt-ROS↑, mitochondrial ROS, were involved in the PL-induced cell death in gastric cancer cells.
"highlight2" >Casp9↑, Notably, caspase-9 activity was significantly elevated after PL treatment in SGC-7901 cells
"highlight2" >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)
"highlight2" >Bcl-xL↓,
"highlight2" >cl‑PARP↑,
"highlight2" >eff↓, Pre-incubation with GSH attenuated these effects confirming their linkage to PL-induced oxidative stress
"highlight2" >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
"highlight2" >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.
"highlight2" >ROS↑, combination of NB and PL significantly induced higher levels of ROS
"highlight2" >BioAv↓, clinical application of PL is limited by its poor cellular uptake.
"highlight2" >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.
"highlight2" >Apoptosis↑, increased apoptosis and enhanced G2/M cycle arrest of C6 glioma cells, compared to PL alone administration.
"highlight2" >TumCCA↑,
"highlight2" >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
"highlight2" >TrxR↓, piperlongumine (PL) and its derivatives have been reported to be inhibitors of TrxR.
"highlight2" >selectivity↑, selective killing effect between normal and cancer cells.
"highlight2" >ROS↑, ZC0101 had the ability to promote cellular ROS accumulation
"highlight2" >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
"highlight2" >selectivity↑, Piperlongumine (PL), a natural alkaloid compound isolated from long pepper (Piper longum), can selectively kill cancer cells, but not normal cells,
"highlight2" >ROS↑, by accumulation of reactive oxygen species (ROS)
"highlight2" >SETBP1↓, PL downregulates SETDB1 expression
"highlight2" >cl‑Casp9↑, enhanced caspase 9 dependent-PARP cleavage during PL-induced cell death.
"highlight2" >eff↓, ROS inhibitor NAC (N-acetyl cysteine) recovered SETDB1 expression decreased by PL.
"highlight2" >FOSB↑, Decreased SETDB1 expression induced transcriptional activity of FosB during PL treatment. PL treatment dramatically increased FosB promoter activity up to 9-fold

992- PL,    Piperlongumine based nanomedicine impairs glycolytic metabolism in triple negative breast cancer stem cells through modulation of GAPDH & FBP1
- in-vivo, BC, NA
"highlight2" >EPR↓,
"highlight2" >Glycolysis↓,
"highlight2" >GAPDH↓,
"highlight2" >GSTP1/GSTπ↝,
"highlight2" >FBPase↑, upregulation of fructose-1,6-bisphosphatase 1 (FBP1), a rate-limiting enzyme in gluconeogenesis.

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
"highlight2" >ROS↑, PL acted as a ROS inducer via binding and inhibiting TrxR (IC50 around 10.17 μM).
"highlight2" >TrxR↓,
"highlight2" >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.
"highlight2" >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
"highlight2" >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).
"highlight2" >selectivity↑, 15-fold selectivity toward A549 cells over normal WI-38 cells.
"highlight2" >TrxR↓, selenoprotein thioredoxin reductase (TrxR) is one of the targets by which PL-CL promotes the ROS generation.
"highlight2" >TumCCA↑, S-phase arrest
"highlight2" >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
"highlight2" >H2O2↑, significant accumulation of ROS (O2.- and H2O2)

2649- PL,    Oxidative Stress Inducers in Cancer Therapy: Preclinical and Clinical Evidence
- Review, Var, NA
"highlight2" >AntiCan↑, investigated for its anticancer activity in various cancer types, including hematological cancers, colorectal, gastric, lung, breast, prostate, and oral cancers, melanoma, and glioma
"highlight2" >ROS↑, Its in vitro anticancer activity can be attributed to induction of ROS through increased glutathione disulfide levels, decreased glutathione levels
"highlight2" >GSH↓,
"highlight2" >TrxR↓, inhibition of thioredoxin reductase (TrxR), an enzyme which reduces thioredoxin, a redox protein that protects against oxidative stress
"highlight2" >Trx↓,
"highlight2" >Apoptosis↑, PPL-mediated ROS accumulation further leads to ROS-mediated apoptosis
"highlight2" >TumCCA↑, G1 or G2/M cell cycle arrest
"highlight2" >ER Stress↑, ER stress
"highlight2" >DNAdam↑, oxidative DNA damage
"highlight2" >ChemoSen↑, PPL was reported to sensitize head and neck, gastric, and liver cancers to cisplatin [18], oxaliplatin [19], and sorafenib [20], respectively
"highlight2" >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
"highlight2" >ROS↑, characterized as an inducer of reactive oxygen species (ROS)
"highlight2" >TumCP↓, 5-15 μM piperlongumine inhibited cell proliferation and induced apoptosis and ROS,
"highlight2" >Apoptosis↑,
"highlight2" >eff↓, these responses were attenuated after cotreatment with the antioxidant glutathione
"highlight2" >Sp1/3/4↓, Piperlongumine also downregulated expression of Sp1, Sp3, Sp4
"highlight2" >cycD1/CCND1↓, and several pro-oncogenic Sp-regulated genes including cyclin D1, survivin, cMyc, epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (cMet)
"highlight2" >survivin↓,
"highlight2" >cMyc↓,
"highlight2" >EGFR↓,
"highlight2" >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
"highlight2" >ROS↑, . Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death
"highlight2" >Apoptosis↑,
"highlight2" >selectivity↑, but it has little effect on either rapidly or slowly dividing primary normal cells
"highlight2" >*ROS∅, In contrast, PL did not cause an increase in ROS levels in normal cells
"highlight2" >GSH↓, lead to a decrease in GSH and an increase in GSSG levels in cancer cells
"highlight2" >GSSG↑,
"highlight2" >H2O2↑, we found that hydrogen peroxide and nitric oxide, but not superoxide anion, were among the ROS species induced by PL in cancer cells
"highlight2" >NO↑,
"highlight2" >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
"highlight2" >ROS↑, known to selectively kill tumor cells via perturbation of reactive oxygen species (ROS) homeostasis
"highlight2" >GSH↓, PL induced excessive production of ROS due to depletion of glutathione and inhibition of thioredoxin reductase
"highlight2" >TrxR↓,
"highlight2" >RadioS↑, PL enhanced both the intrinsic and hypoxic radiosensitivity of tumor cells
"highlight2" >DNAdam↑, inked to ROS-mediated increase of DNA damage, G2/M cell cycle arrest, and inhibition of cellular respiration
"highlight2" >TumCCA↑,
"highlight2" >mitResp↓,
"highlight2" >GSTs↓, PL proved to perturb GSH system by inhibition of glutathione S-transferase (GST) that catalyzes the conjugation of GSH with its substrate
"highlight2" >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
"highlight2" >TrxR1?, known to inhibit the cytosolic thioredoxin reductase (TXNRD1 or TrxR1) and selectively kill cancer cells.
"highlight2" >TumCD↑,
"highlight2" >ROS↑, Piperlongumine Induces ROS-Dependent Cancer Cell Death but Not Ferroptosis
"highlight2" >GSH↓, we found that piperlongumine decreased the cellular GSH contents
"highlight2" >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
"highlight2" >ROS↑, it is selectively toxic to cancer cells by generating reactive oxygen species (ROS)
"highlight2" >selectivity↑,
"highlight2" >tumCV↓, Cell viability, colony formation, cell cycle, apoptosis, and cellular ROS induction.
"highlight2" >TumCCA↑,
"highlight2" >Apoptosis↑,
"highlight2" >ERK↑, activation of Erk and the suppression of the Akt/mTOR pathways through ROS induction were seen in cells treated with PL
"highlight2" >Akt↓,
"highlight2" >mTOR↓,
"highlight2" >neuroP↑, neuroprotective, and anticancer properties
"highlight2" >Bcl-2↓, induces the downregulation of Bcl2 expression and the activation of caspase-3, poly (ADP-ribose) polymerase (PARP), and JNK
"highlight2" >Casp3↑,
"highlight2" >PARP↑,
"highlight2" >JNK↑,
"highlight2" >*toxicity↓, several whole-animal models, and it is highly safe when used in vivo
"highlight2" >eff↓, Pre-treatment with N-acetylcysteine (NAC; a selective ROS scavenger) significantly reduced PL-mediated ROS activation
"highlight2" >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
"highlight2" >ROS↑, Piperlongumine (PL) kills intestinal cancer cells by elevating ROS levels.
"highlight2" >SMAD4↑, PL significantly up-regulates SMAD4 expression, leading to apoptosis in cancer cells.
"highlight2" >ChemoSen↑, PL with Paclitaxel can be a better option for chemotherapy.
"highlight2" >P53↑, Remarkably, P53, P21, BAX, and SMAD4 were significantly upregulated after PL treatment whereas; BCL2 and SURVIVIN were down-regulated.
"highlight2" >P21↑,
"highlight2" >BAX↑,
"highlight2" >Bcl-2↓,
"highlight2" >survivin↓,
"highlight2" >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
"highlight2" >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
"highlight2" >GSH↓, reduced glutathione (GSH) levels in mouse colon cancer cells
"highlight2" >DNAdam↑,
"highlight2" >ChemoSen↑, combined treatment with piperlongumine potentiates the anticancer activity of conventional chemotherapeutics and overcomes resistance to chemo- and radio- therapy
"highlight2" >RadioS↑, piperlongumine treatment enhances ROS production via decreasing GSH levels and causing thioredoxin reductase inhibition
"highlight2" >BioEnh↑, Moreover, the bioavailability is significantly improved after oral administration of piperlongumine
"highlight2" >selectivity↑, It shows selectivity toward human cancer cells over normal cells and has minimal side effects
"highlight2" >BioAv↓, ts low aqueous solubility affects its anti-cancer activity by limiting its bioavailability during oral administration
"highlight2" >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
"highlight2" >p‑Akt↓, Fig 2
"highlight2" >mTOR↓,
"highlight2" >GSK‐3β↓,
"highlight2" >β-catenin/ZEB1↓,
"highlight2" >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)
"highlight2" >Glycolysis↓,
"highlight2" >Cyt‑c↑,
"highlight2" >Casp9↑,
"highlight2" >Casp3↑,
"highlight2" >Casp7↑,
"highlight2" >cl‑PARP↑,
"highlight2" >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
"highlight2" >ER Stress↑,
"highlight2" >ATF4↝,
"highlight2" >CHOP↑, activating the downstream ER-MAPK-C/EBP homologous protein (CHOP) signaling pathway
"highlight2" >Prx4↑, piperlongumine kills high-grade glioma cells via oxidative inactivation of PRDX4 mediated ROS induction, thereby inducing intracellular ER stress
"highlight2" >NF-kB↓, piperlongumine treatment (2.5–5 mg/ kg body weight) decreases the growth of lung tumors via inhibition of NF-κB
"highlight2" >cycD1/CCND1↓, decreases expression of cyclin D1, cyclin- dependent kinase (CDK)-4, CDK-6, p- retinoblastoma (p-Rb)
"highlight2" >CDK4↓,
"highlight2" >CDK6↓,
"highlight2" >p‑RB1↓,
"highlight2" >RAS↓, piperlongumine downregulates the expression of Ras protein
"highlight2" >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
"highlight2" >TumCCA↑, by arresting colon tumor cells in the G2/M phase of the cell cycle
"highlight2" >selectivity↑, hows more selective cytotoxicity against human breast cancer MCF-7 cells than human breast epithelial MCF-10A cells
"highlight2" >STAT3↓, thus inducing inhibition of the STAT3 signaling pathway in multiple myeloma cells
"highlight2" >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
"highlight2" >HO-1↑,
"highlight2" >PTEN↑, stimulates ROS accumulation; p53, p27, and PTEN overexpression
"highlight2" >P-gp↓, P-gp, MDR1, MRP1, survivin, p-Akt, NF-κB, and Twist downregulation;
"highlight2" >MDR1↓,
"highlight2" >MRP1↓,
"highlight2" >survivin↓,
"highlight2" >Twist↓,
"highlight2" >AP-1↓, iperlongumine significantly suppresses the expression of transcription factors, such as AP-1, MYC, NF-κB, SP1, STAT1, STAT3, STAT6, and YY1.
"highlight2" >Sp1/3/4↓,
"highlight2" >STAT1↓,
"highlight2" >STAT6↓,
"highlight2" >SOX4↑, increased expression of p21, SOX4, and XBP in B-ALL cells
"highlight2" >XBP-1↑,
"highlight2" >P21↑,
"highlight2" >eff↑, combined use of piperlongumine with cisplatin enhances the sensitivity toward cisplatin by inhibiting Akt phosphorylation
"highlight2" >Inflam↓, inflammation (COX-2, IL6); invasion and metastasis, such as ICAM-1, MMP-9, CXCR-4, VEGF;
"highlight2" >COX2↓,
"highlight2" >IL6↓,
"highlight2" >MMP9↓,
"highlight2" >TumMeta↓,
"highlight2" >TumCI↓,
"highlight2" >ICAM-1↓,
"highlight2" >CXCR4↓,
"highlight2" >VEGF↓,
"highlight2" >angioG↓,
"highlight2" >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
"highlight2" >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
"highlight2" >TumCP↓, exhibits potent activity against various cancer cell proliferation
"highlight2" >Apoptosis↑, Apoptosis, cell cycle arrest, increased ROS generation
"highlight2" >TumCCA↑,
"highlight2" >ROS↑,

2948- PL,    The promising potential of piperlongumine as an emerging therapeutics for cancer
- Review, Var, NA
"highlight2" >tumCV↓, inhibit different hallmarks of cancer such as cell survival, proliferation, invasion, angiogenesis, epithelial-mesenchymal-transition, metastases,
"highlight2" >TumCP↓,
"highlight2" >TumCI↓,
"highlight2" >angioG↓,
"highlight2" >EMT↓,
"highlight2" >TumMeta↓,
"highlight2" >*hepatoP↑, A study demonstrated the hepatoprotective effects of P. longum via decreasing the rate of lipid peroxidation and increasing glutathione (GSH) levels
"highlight2" >*lipid-P↓,
"highlight2" >*GSH↑,
"highlight2" >cardioP↑, cardioprotective effect
"highlight2" >CycB/CCNB1↓, downregulated the mRNA expression of the cell cycle regulatory genes such as cyclin B1, cyclin D1, cyclin-dependent kinases (CDK)-1, CDK4, CDK6, and proliferating cell nuclear antigen (PCNA)
"highlight2" >cycD1/CCND1↓,
"highlight2" >CDK2↓,
"highlight2" >CDK1↓,
"highlight2" >CDK4↓,
"highlight2" >CDK6↓,
"highlight2" >PCNA↓,
"highlight2" >Akt↓, suppression of the Akt/mTOR pathway by PL was also associated with the partial inhibition of glycolysis
"highlight2" >mTOR↓,
"highlight2" >Glycolysis↓,
"highlight2" >NF-kB↓, Suppression of the NF-κB signaling pathway and its related genes by PL was reported in different cancers
"highlight2" >IKKα↓, inactivation of the inhibitor of NF-κB kinase subunit beta (IKKβ)
"highlight2" >JAK1↓, PL efficiently inhibited cell proliferation, invasion, and migration by blocking the JAK1,2/STAT3 signaling pathway
"highlight2" >JAK2↓,
"highlight2" >STAT3↓,
"highlight2" >ERK↓, PL also negatively regulates ERK1/2 signaling pathways, thereby suppressing the level of c-Fos in CRC cells
"highlight2" >cFos↓,
"highlight2" >Slug↓, PL was found to downregulate slug and upregulate E-cadherin and inhibited epithelial-mesenchymal transition (EMT) in breast cancer cells
"highlight2" >E-cadherin↑,
"highlight2" >TOP2↓, ↓topoisomerase II, ↑p53, ↑p21, ↓Bcl-2, ↑Bax, ↑Cyt C, ↑caspase-3, ↑caspase-7, ↑caspase-8
"highlight2" >P53↑,
"highlight2" >P21↑,
"highlight2" >Bcl-2↓,
"highlight2" >BAX↑,
"highlight2" >Casp3↑,
"highlight2" >Casp7↑,
"highlight2" >Casp8↑,
"highlight2" >p‑HER2/EBBR2↓, ↓p-HER1, ↓p-HER2, ↓p-HER3
"highlight2" >HO-1↑, ↑Apoptosis, ↑HO-1, ↑Nrf2
"highlight2" >NRF2↑,
"highlight2" >BIM↑, ↑BIM, ↑cleaved caspase-9 and caspase-3, ↓p-FOXO3A, ↓p-Akt
"highlight2" >p‑FOXO3↓,
"highlight2" >Sp1/3/4↓, ↑apoptosis, ↑ROS, ↓Sp1, ↓Sp3, ↓Sp4, ↓cMyc, ↓EGFR, ↓survivin, ↓cMET
"highlight2" >cMyc↓,
"highlight2" >EGFR↓,
"highlight2" >survivin↓,
"highlight2" >cMET↓,
"highlight2" >NQO1↑, G2/M phase arrest, ↑apoptosis, ↑ROS, ↓p-Akt, ↑Bad, ↓Bcl-2, ↑NQO1, ↑HO-1, ↑SOD2, ↑p21, ↑p-ERK, ↑p-JNK,
"highlight2" >SOD2↑,
"highlight2" >TrxR↓, G2/M cell cycle arrest, ↑apoptosis, ↑ROS, ↓GSH, ↓TrxR
"highlight2" >MDM2↓, ↑ROS, ↓MDM-2, ↓cyclin B1, ↓Cdc2, G2/M phase arrest, ↑p-eIF2α, ↑ATF4, KATO III ↑CHOP, ↑apoptosis
"highlight2" >p‑eIF2α↑,
"highlight2" >ATF4↑,
"highlight2" >CHOP↑,
"highlight2" >MDA↑, ↑ROS, ↓TrxR1, ↑cleaved caspase-3, ↑CHOP, ↑MDA
"highlight2" >Ki-67↓, ↓Ki-67, ↓MMP-9, ↓Twist,
"highlight2" >MMP9↓,
"highlight2" >Twist↓,
"highlight2" >SOX2↓, ↓SOX2, ↓NANOG, ↓Oct-4, ↑E-cadherin, ↑CK18, ↓N-cadherin, ↓vimentin, ↓snail, ↓slug
"highlight2" >Nanog↓,
"highlight2" >OCT4↓,
"highlight2" >N-cadherin↓,
"highlight2" >Vim↓,
"highlight2" >Snail↓,
"highlight2" >TumW↓, ↓Tumor weight, ↓tumor growth
"highlight2" >TumCG↓,
"highlight2" >HK2↓, ↓HK2
"highlight2" >RB1↓, ↓Rb
"highlight2" >IL6↓, ↓IL-6, ↓IL-8,
"highlight2" >IL8↓,
"highlight2" >SOD1↑, ↑SOD1
"highlight2" >RadioS↑, ombination with PL, very low intensity of radiation is found to be effective in cancer cells
"highlight2" >ChemoSen↑, PL as a chemosensitizer which sensitized the cancer cells towards the commercially available chemotherapeutics
"highlight2" >toxicity↓, PL does not have any adverse effect on the normal functioning of the liver and kidney.
"highlight2" >Sp1/3/4↓, In vitro SKBR3 ↓Sp1, ↓Sp3, ↓Sp4
"highlight2" >GSH↓, In vitro MCF-7 ↓CDK1, G2/M phase arrest ↓CDK4, ↓CDK6, ↓PCNA, ↓p-CDK1, ↑cyclin B1, ↑ROS, ↓GSH, ↓p-IκBα,
"highlight2" >SOD↑, In vitro PANC-1, MIA PaCa-2 ↑ROS, ↑SOD1, ↑GSTP1, ↑HO-1

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
"highlight2" >selectivity↑, Piperlongumine (PL) selectively kills GBM cells but not normal astrocytes.
"highlight2" >ROS↑, PL kills GBM cells via ROS accumulation
"highlight2" >JNK↑, JNK and p38 activation contributes to PL’s cytotoxicity in GBM cells.
"highlight2" >p38↑,
"highlight2" >GSH↓, PL elevated ROS prominently and reduced glutathione levels in LN229 and U87 cells.
"highlight2" >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: 56

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

Catalase↓, 1,   Catalase∅, 1,   Ferroptosis↓, 1,   Ferroptosis↑, 2,   GPx↓, 1,   GPx1∅, 1,   GPx4↓, 1,   GSH?, 1,   GSH↓, 18,   GSSG↑, 3,   GSTP1/GSTπ↓, 2,   GSTP1/GSTπ↝, 1,   GSTs↓, 1,   H2O2↑, 3,   HO-1↑, 4,   Keap1↓, 1,   Keap1↝, 1,   lipid-P↑, 4,   MDA↓, 1,   MDA↑, 1,   NQO1↑, 1,   NRF2↓, 1,   NRF2↑, 5,   Prx4↓, 1,   Prx4↑, 1,   PrxII↓, 1,   ROS?, 1,   ROS↑, 40,   mt-ROS↑, 1,   SOD↑, 1,   SOD∅, 1,   SOD1↑, 2,   SOD2↑, 1,   Trx↓, 2,   Trx1↓, 1,   TrxR↓, 9,   TrxR1?, 1,   TrxR1↓, 3,  

Metal & Cofactor Biology ⓘ

FTH1↓, 1,  

Mitochondria & Bioenergetics ⓘ

mitResp↓, 1,   MMP↓, 3,   mtDam↑, 1,  

Core Metabolism/Glycolysis ⓘ

cMyc↓, 4,   FBPase↑, 1,   GAPDH↓, 1,   Glycolysis↓, 3,   HK2↓, 2,   IDO1↓, 1,   LDH↓, 1,   NAD↑, 1,  

Cell Death ⓘ

Akt↓, 5,   p‑Akt↓, 3,   Apoptosis↑, 10,   BAX↓, 1,   BAX↑, 2,   Bcl-2↓, 7,   Bcl-xL↓, 1,   BIM↑, 1,   cl‑Casp1↓, 1,   cl‑Casp1↑, 1,   Casp3↑, 5,   cl‑Casp3↑, 1,   cl‑Casp3∅, 1,   proCasp3↓, 1,   Casp7↑, 2,   Casp8↑, 1,   Casp9↑, 2,   cl‑Casp9↑, 1,   Cyt‑c↑, 2,   Ferroptosis↓, 1,   Ferroptosis↑, 2,   GSDMD↑, 1,   JNK↑, 4,   MAPK↑, 2,   Mcl-1↓, 1,   MDM2↓, 1,   p38↑, 6,   PUMA↑, 1,   Pyro↑, 1,   survivin↓, 4,   TumCD↑, 1,  

Kinase & Signal Transduction ⓘ

p‑HER2/EBBR2↓, 1,   Sp1/3/4↓, 5,  

Transcription & Epigenetics ⓘ

other⇅, 1,   SETBP1↓, 1,   tumCV↓, 3,  

Protein Folding & ER Stress ⓘ

CHOP↑, 5,   p‑eIF2α↑, 1,   ER Stress↑, 7,   p‑PERK↑, 1,   UPR↑, 1,   XBP-1↑, 1,  

DNA Damage & Repair ⓘ

DNAdam↑, 6,   DNMT1↑, 1,   GADD45A↑, 1,   P53↑, 2,   PARP↑, 1,   cl‑PARP↑, 4,   cl‑PARP∅, 1,   PCNA↓, 2,  

Cell Cycle & Senescence ⓘ

CDK1↓, 1,   CDK2↓, 1,   CDK4↓, 2,   CycB/CCNB1↓, 1,   cycD1/CCND1↓, 4,   P21↑, 5,   RB1↓, 1,   p‑RB1↓, 1,   TumCCA↑, 15,  

Proliferation, Differentiation & Cell State ⓘ

cFos↓, 1,   cMET↓, 3,   EMT↓, 3,   ERK↓, 1,   ERK↑, 1,   p‑ERK↓, 1,   FOXM1↓, 1,   p‑FOXO3↓, 1,   GSK‐3β↓, 1,   HDAC↓, 1,   mTOR↓, 5,   Nanog↓, 1,   OCT4↓, 1,   PI3K↓, 1,   PTEN↑, 1,   RAS↓, 1,   SOX2↓, 1,   STAT1↓, 1,   STAT3↓, 4,   STAT6↓, 1,   TOP2↓, 1,   TumCG↓, 4,  

Migration ⓘ

AntiAg↑, 2,   AP-1↓, 1,   Ca+2↑, 1,   CLDN1↓, 1,   E-cadherin↑, 2,   F-actin↓, 1,   FOSB↑, 1,   Ki-67↓, 2,   MMP13↓, 1,   MMP2↓, 2,   MMP3↓, 1,   MMP9↓, 3,   N-cadherin↓, 2,   Slug↓, 3,   SMAD4↑, 1,   Snail↓, 1,   SOX4↑, 1,   TumCI↓, 6,   TumCMig↓, 6,   TumCP↓, 7,   TumMeta↓, 4,   Twist↓, 2,   TXNIP↑, 1,   Vim↓, 1,   Zeb1↓, 2,   ZO-1↓, 1,   β-catenin/ZEB1↓, 2,  

Angiogenesis & Vasculature ⓘ

angioG↓, 2,   ATF4↑, 2,   ATF4↝, 1,   EGFR↓, 2,   EPR↓, 1,   HIF2a↓, 1,   NO↓, 1,   NO↑, 2,   VEGF↓, 1,  

Barriers & Transport ⓘ

P-gp↓, 1,  

Immune & Inflammatory Signaling ⓘ

ASC↑, 1,   COX2↓, 1,   CXCR4↓, 1,   ICAM-1↓, 1,   IKKα↓, 2,   IKKα↑, 1,   IL1β↓, 1,   IL6↓, 3,   IL8↓, 1,   Inflam↓, 4,   JAK1↓, 1,   JAK2↓, 1,   MCP1↓, 1,   NF-kB↓, 4,   NF-kB↑, 1,   PGE2↓, 1,  

Protein Aggregation ⓘ

NLRP3↓, 1,   NLRP3↑, 1,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 1,   CDK6↓, 2,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 4,   BioAv↑, 4,   BioEnh↑, 2,   ChemoSen↑, 5,   Dose↓, 1,   Dose↝, 2,   eff↓, 10,   eff↑, 14,   eff↝, 1,   Half-Life?, 1,   Half-Life↝, 1,   MDR1↓, 1,   MRP1↓, 1,   RadioS↑, 3,   selectivity↑, 19,  

Clinical Biomarkers ⓘ

AR↓, 1,   EGFR↓, 2,   FOXM1↓, 1,   p‑HER2/EBBR2↓, 1,   IL6↓, 3,   Ki-67↓, 2,   LDH↓, 1,  

Functional Outcomes ⓘ

AntiCan↑, 1,   AntiTum↑, 1,   cardioP↑, 1,   K17↓, 1,   memory↑, 1,   neuroP↑, 3,   OS↑, 1,   toxicity↓, 2,   toxicity↑, 1,   toxicity∅, 1,   TumW↓, 2,  
Total Targets: 221

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

GSH↑, 2,   GSSG∅, 1,   GSTA1↓, 1,   HO-1↑, 1,   lipid-P↓, 1,   NQO1↑, 1,   NRF2↑, 1,   NRF2⇅, 1,   Prx4∅, 1,   ROS↓, 1,   ROS↑, 1,   ROS∅, 2,   Trx↑, 1,   TrxR↑, 1,  

Core Metabolism/Glycolysis ⓘ

SIRT1↑, 1,  

Cell Death ⓘ

iNOS↓, 1,  

Transcription & Epigenetics ⓘ

other↝, 1,  

Migration ⓘ

MMP13↓, 1,   MMP3↑, 1,   VCAM-1↓, 1,   α-tubulin↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   Hif1a↓, 2,   NO↓, 1,   VEGF↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   ICAM-1↓, 1,   IL17↓, 1,   IL1β↓, 1,   IL22↓, 1,   IL6↓, 1,   Inflam↓, 4,   PGE2↓, 1,   TNF-α↓, 1,  

Protein Aggregation ⓘ

Aβ↓, 1,   NLRP3↓, 1,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 1,   BioAv↑, 3,   eff↓, 1,   eff↑, 1,   Half-Life↑, 1,  

Clinical Biomarkers ⓘ

IL6↓, 1,  

Functional Outcomes ⓘ

cognitive↑, 1,   hepatoP↑, 1,   neuroP↑, 2,   toxicity↓, 2,  
Total Targets: 46

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#:%  State#:%  Dir#:%
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