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


ChemoSen, chemo-sensitization: Click to Expand ⟱
Source:
Type:
The effectiveness of chemotherapy by increasing cancer cell sensitivity to the drugs used to treat them, which is known as “chemo-sensitization”.

Chemo-Sensitizers:
-Curcumin
-Resveratrol
-EGCG
-Quercetin
-Genistein
-Berberine
-Piperine: alkaloid from black pepper
-Ginsenosides: active components of ginseng
-Silymarin
-Allicin
-Lycopene
-Ellagic acid
-caffeic acid phenethyl ester
-flavopiridol
-oleandrin
-ursolic acid
-butein
-betulinic acid
Scientific Papers found: Click to Expand⟱
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

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

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

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: 5

Results for Effect on Cancer/Diseased Cells:
Akt↓,1,   p‑Akt↓,1,   angioG↓,2,   AntiCan↑,1,   AP-1↓,1,   Apoptosis↑,1,   ATF4↑,1,   ATF4↝,1,   BAX↑,2,   Bcl-2↓,2,   BIM↑,1,   BioAv↓,2,   BioAv↑,1,   BioEnh↑,1,   cardioP↑,1,   Casp3↑,2,   Casp7↑,2,   Casp8↑,1,   Casp9↑,1,   CDK1↓,1,   CDK2↓,1,   CDK4↓,2,   CDK6↓,2,   cFos↓,1,   ChemoSen↑,5,   CHOP↑,2,   cMET↓,1,   cMyc↓,2,   COX2↓,1,   CXCR4↓,1,   CycB↓,1,   cycD1↓,2,   Cyt‑c↑,1,   DNAdam↑,2,   E-cadherin↑,1,   eff↑,3,   EGFR↓,1,   p‑eIF2α↑,1,   EMT↓,1,   ER Stress↑,2,   ERK↓,1,   p‑FOXO3↓,1,   Glycolysis↓,2,   GSH↓,4,   GSK‐3β↓,1,   GSSG↑,1,   GSTP1/GSTπ↓,1,   Half-Life↝,1,   p‑HER2/EBBR2↓,1,   HK2↓,2,   HO-1↑,2,   ICAM-1↓,1,   IKKα↓,1,   IL6↓,2,   IL8↓,1,   Inflam↓,1,   JAK1↓,1,   JAK2↓,1,   Ki-67↓,1,   MDA↑,1,   MDM2↓,1,   MDR1↓,1,   MMP9↓,2,   MRP1↓,1,   mTOR↓,2,   N-cadherin↓,1,   NA↓,1,   Nanog↓,1,   NF-kB↓,2,   NQO1↑,1,   NRF2↑,2,   OCT4↓,1,   P-gp↓,1,   P21↑,3,   P53↑,2,   cl‑PARP↑,2,   PCNA↓,1,   Prx4↑,1,   PTEN↑,1,   PUMA↑,1,   RadioS↑,2,   RAS↓,1,   RB1↓,1,   p‑RB1↓,1,   ROS↑,4,   selectivity↑,3,   Slug↓,1,   SMAD4↑,1,   Snail↓,1,   SOD↑,1,   SOD1↑,1,   SOD2↑,1,   SOX2↓,1,   SOX4↑,1,   Sp1/3/4↓,3,   STAT1↓,1,   STAT3↓,2,   STAT6↓,1,   survivin↓,3,   TOP2↓,1,   toxicity↓,1,   toxicity↑,1,   Trx↓,1,   TrxR↓,3,   TumCCA↑,2,   TumCG↓,1,   TumCI↓,2,   TumCMig↓,1,   TumCP↓,1,   tumCV↓,1,   TumMeta↓,2,   TumW↓,1,   Twist↓,2,   VEGF↓,1,   Vim↓,1,   XBP-1↑,1,   β-catenin/ZEB1↓,1,  
Total Targets: 117

Results for Effect on Normal Cells:
GSH↑,1,   GSSG∅,1,   hepatoP↑,1,   lipid-P↓,1,  
Total Targets: 4

Scientific Paper Hit Count for: ChemoSen, chemo-sensitization
5 Piperlongumine
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:134  Target#:1106  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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