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


TumCI, Tumor Cell invasion: Click to Expand ⟱
Source:
Type:
Tumor cell invasion is a critical process in cancer progression and metastasis, where cancer cells spread from the primary tumor to surrounding tissues and distant organs. This process involves several key steps and mechanisms:

1.Epithelial-Mesenchymal Transition (EMT): Many tumors originate from epithelial cells, which are typically organized in layers. During EMT, these cells lose their epithelial characteristics (such as cell-cell adhesion) and gain mesenchymal traits (such as increased motility). This transition is crucial for invasion.

2.Degradation of Extracellular Matrix (ECM): Tumor cells secrete enzymes, such as matrix metalloproteinases (MMPs), that degrade the ECM, allowing cancer cells to invade surrounding tissues. This degradation facilitates the movement of cancer cells through the tissue.

3.Cell Migration: Once the ECM is degraded, cancer cells can migrate. They often use various mechanisms, including amoeboid movement and mesenchymal migration, to move through the tissue. This migration is influenced by various signaling pathways and the tumor microenvironment.

4.Angiogenesis: As tumors grow, they require a blood supply to provide nutrients and oxygen. Tumor cells can stimulate the formation of new blood vessels (angiogenesis) through the release of growth factors like vascular endothelial growth factor (VEGF). This not only supports tumor growth but also provides a route for cancer cells to enter the bloodstream.

5.Invasion into Blood Vessels (Intravasation): Cancer cells can invade nearby blood vessels, allowing them to enter the circulatory system. This step is crucial for metastasis, as it enables cancer cells to travel to distant sites in the body.

6.Survival in Circulation: Once in the bloodstream, cancer cells must survive the immune response and the shear stress of blood flow. They can form clusters with platelets or other cells to evade detection.

7.Extravasation and Colonization: After traveling through the bloodstream, cancer cells can exit the circulation (extravasation) and invade new tissues. They may then establish secondary tumors (metastases) in distant organs.

8.Tumor Microenvironment: The surrounding microenvironment plays a significant role in tumor invasion. Factors such as immune cells, fibroblasts, and signaling molecules can either promote or inhibit invasion and metastasis.
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↓,

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↑,

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,

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

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

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


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 6

Results for Effect on Cancer/Diseased Cells:
Akt↓,1,   p‑Akt↓,1,   angioG↓,2,   AntiAg↑,1,   AP-1↓,1,   AR↓,1,   ASC↑,1,   ATF4↑,1,   ATF4↝,1,   BAX↑,1,   Bcl-2↓,2,   BIM↑,1,   BioAv↓,1,   BioAv↑,1,   BioEnh↑,1,   Ca+2↑,1,   cardioP↑,1,   cl‑Casp1↑,1,   Casp3↑,3,   Casp7↑,2,   Casp8↑,1,   Casp9↑,1,   CDK1↓,1,   CDK2↓,1,   CDK4↓,2,   CDK6↓,2,   cFos↓,1,   ChemoSen↑,2,   CHOP↑,3,   CLDN1↓,1,   cMET↓,1,   cMyc↓,3,   COX2↓,1,   CXCR4↓,1,   CycB↓,1,   cycD1↓,2,   Cyt‑c↑,1,   DNAdam↑,2,   Dose↝,1,   E-cadherin↑,1,   eff↓,1,   eff↑,2,   EGFR↓,1,   p‑eIF2α↑,1,   EMT↓,2,   ER Stress↑,2,   ERK↓,1,   F-actin↓,1,   Foxm1↓,1,   p‑FOXO3↓,1,   Glycolysis↓,2,   GSDMD↑,1,   GSH↓,5,   GSK‐3β↓,1,   Half-Life↝,1,   p‑HER2/EBBR2↓,1,   HK2↓,2,   HO-1↑,2,   ICAM-1↓,1,   IKKα↓,1,   IL6↓,2,   IL8↓,1,   Inflam↓,2,   JAK1↓,1,   JAK2↓,1,   JNK↑,1,   Ki-67↓,1,   MAPK↑,1,   Mcl-1↓,1,   MDA↑,1,   MDM2↓,1,   MDR1↓,1,   MMP13↓,1,   MMP3↓,1,   MMP9↓,2,   MRP1↓,1,   mTOR↓,2,   N-cadherin↓,2,   NA↓,1,   Nanog↓,1,   neuroP↑,1,   NF-kB↓,2,   NF-kB↑,1,   NLRP3↑,1,   NO↓,1,   NQO1↑,1,   NRF2↓,1,   NRF2↑,2,   OCT4↓,1,   P-gp↓,1,   P21↑,2,   p38↑,1,   P53↑,1,   cl‑PARP↑,1,   PCNA↓,1,   PGE2↓,1,   Prx4↑,1,   PTEN↑,1,   Pyro↑,1,   RadioS↑,2,   RAS↓,1,   RB1↓,1,   p‑RB1↓,1,   ROS↑,5,   selectivity↑,3,   Slug↓,2,   Snail↓,1,   SOD↑,1,   SOD1↑,1,   SOD2↑,1,   SOX2↓,1,   SOX4↑,1,   Sp1/3/4↓,3,   STAT1↓,1,   STAT3↓,3,   STAT6↓,1,   survivin↓,2,   TOP2↓,1,   toxicity↓,1,   Trx↓,1,   TrxR↓,2,   TrxR1↓,1,   TumCCA↑,2,   TumCG↓,1,   TumCI↓,6,   TumCMig↓,4,   TumCP↓,3,   tumCV↓,2,   TumMeta↓,2,   TumW↓,1,   Twist↓,2,   TXNIP↑,1,   VEGF↓,1,   Vim↓,1,   XBP-1↑,1,   Zeb1↓,1,   ZO-1↓,1,   β-catenin/ZEB1↓,2,  
Total Targets: 138

Results for Effect on Normal Cells:
GSH↑,1,   hepatoP↑,1,   lipid-P↓,1,  
Total Targets: 3

Scientific Paper Hit Count for: TumCI, Tumor Cell invasion
6 Piperlongumine
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:134  Target#:324  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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