Database Query Results : Fisetin, , NF-kB

FIS, Fisetin: Click to Expand ⟱
Features:
Fisetin is a plant based flavonoid. Found in strawberries(160ug/g), apples, persimmons, onions, cucumbers, grapes.

-Note half-life 3-4hrs
- Oral BioAv low (40-50%)
Pathways:
- induce ROS production in cancer cells, but also known to reduce it.
Also a claim Fisetin-Induced Reactive Oxygen Species Production Has No Effect on Apoptosis in RCC cells
Also one claim (NAC 10-20mM levels) that NAC enhances ROS/apoptosis
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓
- Does not appear to lower antioxidants in cancer cells
- Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓">NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : IL-1β↓, TNF-α↓, IL-6↓,
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, IGF-1↓, uPA↓, VEGF↓, FAK↓, RhoA↓, NF-κB↓, TGF-β↓, ERK↓
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, FAK↓, ERK↓, EMT↓, TOP1↓, TET1↓,
- inhibits HIF-1α↓, cMyc↓, LDH↓, GRP78↑,
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓,
- inhibits Cancer Stem Cells : CD133↓, β-catenin↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK↓, ERK↓, JNK,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,

- Selectivity: Cancer Cells vs Normal Cells

Fisetin effect on Cancer Cells
Rank Pathway / Axis Cancer Cells Normal Cells Label Primary Interpretation Notes
1 PI3K → AKT → mTOR axis ↓ AKT / ↓ mTOR signaling ↔ adaptive suppression Driver Loss of survival and growth signaling Fisetin consistently suppresses pro-survival PI3K/AKT signaling, supporting growth inhibition and sensitization to stress
2 NF-κB signaling ↓ NF-κB activation ↓ inflammatory NF-κB tone Driver Suppression of inflammatory survival transcription NF-κB inhibition contributes to anti-inflammatory effects and reduced tumor-supportive signaling
3 Reactive oxygen species (ROS) ↑ ROS (context- & dose-dependent) ↓ ROS Conditional Driver Biphasic redox modulation Fisetin can act as a pro-oxidant in cancer cells at higher stress/dose while remaining antioxidant in normal cells
4 Mitochondrial integrity / intrinsic apoptosis ↓ ΔΨm; ↑ caspase activation ↔ preserved Secondary Execution of intrinsic apoptosis Mitochondrial apoptosis occurs downstream of signaling and redox disruption
5 Cell cycle regulation ↑ G1 or G2/M arrest ↔ spared Phenotypic Cytostatic growth control Cell-cycle arrest reflects upstream pathway inhibition rather than direct CDK blockade
6 Senescence / senolytic action ↑ senescence clearance (senescent-like tumor/stroma subsets) ↓ senescent cell burden (selective) Secondary Selective vulnerability of senescent-like cells Fisetin is commonly described as senolytic; in cancer context this may impact tumor microenvironment and therapy-induced senescence
7 MAPK stress signaling (JNK / p38) ↑ JNK / ↑ p38 (context-dependent) ↔ minimal Secondary Stress-mediated apoptosis signaling MAPK activation often follows ROS increase and supports apoptotic signaling
8 NRF2 antioxidant response ↑ NRF2 (adaptive, context-dependent) ↑ NRF2 (protective) Adaptive Stress compensation NRF2 activation reflects redox buffering responses rather than primary cytotoxicity
9 Migration / invasion (EMT, MMP axis) ↓ migration & invasion ↔ Phenotypic Anti-metastatic phenotype Reduced EMT and protease activity limit invasive behavior downstream of signaling changes


NF-kB, Nuclear factor kappa B: Click to Expand ⟱
Source: HalifaxProj(inhibit)
Type:
NF-kB signaling
Nuclear factor kappa B (NF-κB) is a transcription factor that plays a crucial role in regulating immune response, inflammation, cell proliferation, and survival.
NF-κB is often found to be constitutively active in many types of cancer cells. This persistent activation can promote tumorigenesis by enhancing cell survival, proliferation, and metastasis.
Scientific Papers found: Click to Expand⟱
2850- FIS,    Fisetin regulates TPA-induced breast Cancer cell invasion by suppressing matrix metalloproteinase-9 activation via the PKC/ROS/MAPK pathways
- in-vitro, BC, MCF-7
TumCI↓, Fisetin significantly attenuated TPA-induced cell invasion in MCF-7 human breast cancer cells, and was found to inhibit the activation of the PKCα/ROS/ERK1/2 and p38 MAPK signaling pathways.
PKCδ↓,
ROS↓,
ERK↑,
p38↓,
NF-kB↓, reduced NF-κB activation
MMP9↓, reduced TPA activation of PKCα/ROS/ERK1/2 and p38 MAPK signals, ultimately leading to the downregulation of MMP-9 expression.

2852- FIS,    A comprehensive view on the fisetin impact on colorectal cancer in animal models: Focusing on cellular and molecular mechanisms
- Review, CRC, NA
Risk↓, Flavonoids, including fisetin, have been linked to a reduced risk of colorectal cancer (CRC)
P53↑, increased levels of p53 and decreased levels of murine double minute 2, contributing to apoptosis induction
MDM2↓,
COX2↓, fisetin inhibits the cyclooxygenase-2 and wingless-related integration site (Wnt)/epidermal growth factor receptor/nuclear factor kappa B signaling pathways
Wnt↓,
NF-kB↓,
CDK2↓, regulating the activities of cyclin-dependent kinase 2 and cyclin-dependent kinase 4, reducing retinoblastoma protein phosphorylation, decreasing cyclin E levels, and increasing p21 levels
CDK4↓,
p‑RB1↓,
cycE/CCNE↓,
P21↑,
NRF2↓, Pandey and Trigun revealed that fisetin induces apoptosis in CRC cells by inhibiting autophagy and suppressing Nrf2
ROS↑, Furthermore, fisetin elevated ROS levels and downregulated Nrf2 expression, indicating Nrf2 suppression in fisetin-induced apoptosis in CRC cells.
Casp8↑, fisetin treatment resulted in the upregulation of various molecular pathways, including cleaved caspase-8, Fas ligand, TRAIL, and DR5 levels, in the cancer cells
Fas↑,
TRAIL↑,
DR5↑,
MMP↓, Fisetin also caused mitochondrial membrane depolarization, leading to the release of Smac/DIABLO and cytochrome c
Cyt‑c↑,
selectivity↑, enhanced cellular uptake, and induction of apoptosis in cancer cells
P450↝, Fisetin also affected the activities of cytochrome P450 (CYP450 3A4) and glutathione-S-transferase
GSTs↝,
RadioS↑, fisetin pretreatment heightened the radiosensitivity of p53-mutant HT29 human CRC cells
Inflam↓, Fisetin suppresses inflammation in the colon and CRC
β-catenin/ZEB1↓, fisetin in treating colon cancer, revealing its capability to effectively downregulate β-catenin and COX-2
EGFR↓, fisetin decreased EGFR and NF-κB activation in HT29 cells
TumCCA↑, It induces cell cycle arrest, disrupting the transition from the G1 to the S phase, as well as causing G2/M phase arrest
ChemoSen↑, intervention with fisetin and 5-FU appeared to extend the lifespan of the experimental animals

2845- FIS,    Fisetin: A bioactive phytochemical with potential for cancer prevention and pharmacotherapy
- Review, Var, NA
PI3K↓, block multiple signaling pathways such as the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) and p38
Akt↓,
mTOR↓,
p38↓,
*antiOx↑, antioxidant, anti-inflammatory, antiangiogenic, hypolipidemic, neuroprotective, and antitumor effect
*neuroP↑,
Casp3↑, U266 cancer cell line through activation of caspase-3, downregulation of Bcl-2 and Mcl-1L, upregulation of Bax, Bim and Bad
Bcl-2↓,
Mcl-1↓,
BAX↑,
BIM↑,
BAD↑,
AMPK↑, activation of 5'adenosine monophosphate-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC) and decreased phosphorylation of AKT and mTOR were also observed
ACC↑,
DNAdam↑, DNA fragmentation, mitochondrial membrane depolarizatio
MMP↓,
eff↑, fisetin in combination with a citrus flavanone, hesperetin mediated apoptosis by mitochondrial membrane depolarization and caspase-3 act
ROS↑, NCI-H460 human non-small cell lung cancer line, fisetin generated reactive oxygen species (ROS), endoplasmic reticulum (ER) stress
cl‑PARP↑, fisetin treatment resulted in PARP cleavage
Cyt‑c↑, release of cyt. c
Diablo↑, release of cyt. c and Smac/DIABLO from mitochondria,
P53↑, increased p53 protein levels
p65↓, reduced phospho-p65 and Myc oncogene expression
Myc↓,
HSP70/HSPA5↓, fisetin causes inhibition of proliferation by the modulation of heat shock protein 70 (HSP70), HSP27
HSP27↓,
COX2↓, anti-proliferative effects of fisetin through the activation of apoptosis via inhibition of cyclooxygenase-2 (COX-2) and Wnt/EGFR/NF-κB signaling pathways
Wnt↓,
EGFR↓,
NF-kB↓,
TumCCA↑, The anti-proliferative effects of fisetin and hesperetin were shown to be occurred through S, G2/M, and G0/G1 phase arrest in K562 cell progression
CDK2↓, decrease in levels of cyclin D1, cyclin A, Cdk-4 and Cdk-2
CDK4↓,
cycD1/CCND1↓,
cycA1/CCNA1↓,
P21↑, increase in p21 CIP1/WAF1 levels in HT-29 human colon cancer cell
MMP2↓, fisetin has exhibited tumor inhibitory effects by blocking matrix metalloproteinase-2 (MMP- 2) and MMP-9 at mRNA and protein levels,
MMP9↓,
TumMeta↓, Antimetastasis
MMP1↓, fisetin also inhibited the MMP-14, MMP-1, MMP-3, MMP-7, and MMP-9
MMP3↓,
MMP7↓,
MET↓, promotion of mesenchymal to epithelial transition associated with a decrease in mesenchymal markers i.e. N-cadherin, vimentin, snail and fibronectin and an increase in epithelial markers i.e. E-cadherin
N-cadherin↓,
Vim↓,
Snail↓,
Fibronectin↓,
E-cadherin↑,
uPA↓, fisetin suppressed the expression and activity of urokinase plasminogen activator (uPA)
ChemoSen↑, combination treatment of fisetin and sorafenib reduced the migration and invasion of BRAF-mutated melanoma cells both in in-vitro
EMT↓, inhibited epithelial to mesenchymal transition (EMT) as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin
Twist↓, inhibited expression of Snail1, Twist1, Slug, ZEB1 and MMP-2 and MMP-9
Zeb1↓,
cFos↓, significant decrease in NF-κB, c-Fos, and c-Jun levels
cJun↓,
EGF↓, Fisetin inhibited epidermal growth factor (EGF)
angioG↓, Antiangiogenesis
VEGF↓, decreased expression of endothelial nitric oxide synthase (eNOS) and VEGF, EGFR, COX-2
eNOS↓,
*NRF2↑, significantly increased nuclear translocation of Nrf2 and antioxidant response element (ARE) luciferase activity, leading to upregulation of HO-1 expression
HO-1↑,
NRF2↓, Fisetin also triggered the suppression of Nrf2
GSTs↓, declined placental type glutathione S-transferase (GST-p) level in the liver of the fisetin- treated rats with hepatocellular carcinoma (HCC)
ATF4↓, Fisetin also rapidly increased the levels of both Nrf2 and ATF4

2857- FIS,    A review on the chemotherapeutic potential of fisetin: In vitro evidences
- Review, Var, NA
COX2↓, fisetin altered the expression of cyclooxygenase 2 (COX2) thereby suppressed the secretion of prostaglandin E2 ultimately resulting in the inhibition of epidermal growth factor receptor (EGFR) and NF-κB in human colon cancer cells HT29
PGE2↓,
EGFR↓,
Wnt↓, fisetin treatment inhibited the stimulation of Wnt signaling pathway via downregulating the expression of β-catenin and Tcell factor (TCF) 4
β-catenin/ZEB1↓,
TCF↑,
Apoptosis↑, fisetin triggers apoptosis in U266 cells through multiple pathways: enhancing the activation of caspase-3 and PARP cleavage, decreasing the expression of anti-apoptotic proteins (Bcl-2 and Mcl-1 L ),
Casp3↑,
cl‑PARP↑,
Bcl-2↓,
Mcl-1↓,
BAX↑, ncreasing the expression of pro-apoptotic proteins (Bax, Bim, and Bad)
BIM↑,
BAD↑,
Akt↓, decreasing the phosphorylation of AKT and mTOR and elevating the expression of acetyl CoA carboxylase (ACC
mTOR↓,
ACC↑,
Cyt‑c↑, release the cytochrome c and Smac/Diablo into the cytosol
Diablo↑,
cl‑Casp8↑, fisetin exhibited an increased level of cleaved caspase-8, Fas/Fas ligand, death receptor 5/TRAIL, and p53 levels in HCT-116 cells
Fas↑,
DR5↑,
TRAIL↑,
Securin↓, Securin gets degraded on exposure to fisetin in colon cancer cells.
CDC2↓, fisetin decreased the expression of cell division cycle proteins (CDC2 and CDC25C)
CDC25↓,
HSP70/HSPA5↓, Fisetin induced apoptosis as a result of the downregulation of HSP70 and BAG3 and the inhibition of Bcl-2, Bcl-x L and Mcl-1. T
CDK2↓, AGS 0, 25, 50, 75 μM – 24 and 48 h ↓CDK2, ↓CDK4, ↓cyclin D1, ↑casapse-3 cleavage
CDK4↓,
cycD1/CCND1↓,
MMP2↓, A549 0, 1, 5, 10 μM- 24 and 48 hr: ↓MMP-2, ↓u-PA, ↓NF- κB, ↓c-Fos, ↓c-Jun
uPA↓,
NF-kB↓,
cFos↓,
cJun↓,
MEK↓, ↓ MEK1/2 and ERK1/2 phosphorylation, ↓N-cadherin, ↓vimentin, ↓snail, ↓fibronectin, ↑E-cadherin, ↑desmoglein
p‑ERK↓,
N-cadherin↓,
Vim↓,
Snail↓,
Fibronectin↓,
E-cadherin↓,
NF-kB↑, increased expression of NF-κB p65 leading to apoptosis was due to ROS generation on exposure to fisetin
ROS↑,
DNAdam↑, increased ROS triggered cell death through PARP cleavage, DNA damage and mitochondrial membrane depolarization.
MMP↓,
CHOP↑, Though fisetin upregulated CHOP expression and increased the production of ROS, these events fail to induce apoptosis in Caki cells.
eff↑, 50 μM fisetin + 1 mM melatonin Sk-mel-28 Enhances anti-tumour activity [54] 20 μM fisetin + 1 mM melatonin MeWo Enhances anti-tumour activity [54] 10 μM fisetin + 0.1 μM melatonin A549 Induces autophagic cell death
ChemoSen↑, 20 μM fisetin + 5 μM sorafenib A375, SK-MEL-28 Suppresses invasion and metastasis [44] 40 μM fisetin + 10 μM cisplatin A549, A549-CR Enhances apoptosis

2859- FIS,    The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways
- in-vitro, Liver, HepG2 - NA, Colon, Caco-2
TumCG↓, fisetin induces growth inhibition, and apoptosis in hepatic (HepG-2), colorectal (Caco-2) and pancreatic (Suit-2) cancer cell lines.
other↝, activation of CDKN1A, SEMA3E, GADD45B and GADD45A and down-regulation of TOP2A, KIF20A, CCNB2 and CCNB1 genes.
Casp3↑, Fisetin caused significant increase in activation of caspase 3/7 compared to untreated control
Casp7↑,
PGE2↓, Fisetin inhibits PGE2 production
GSTs↓, GST enzyme activity assay has been carried out. The results showed that fisetin induced enzyme inhibition in a dose dependent manner
Wnt↓, inhibiting Wnt/EGFR/NF-kB and COX-2 signaling pathways
EGFR↓,
NF-kB↓,
COX2↓,
P53↑, induction of p53 and p21
P21↑,
P450↓, Fisetin also was able to inhibit cyctochrome P450 (CYP450 3A4) and glutatihione -S-transferase activity

2861- FIS,    The neuroprotective effects of fisetin, a natural flavonoid in neurodegenerative diseases: Focus on the role of oxidative stress
- Review, Nor, NA - Review, Stroke, NA - Review, Park, NA
*antiOx↑, Fisetin is a flavonoid that exhibits potent antioxidant properties and protects the cells against OS
*ROS↓, The antioxidant properties of this flavonoid diminish oxidative stress, ROS production, neurotoxicity, neuro-inflammation, and neurological disorders.
*neuroP↑,
*NO↑, inhibits NO production.
BioAv↝, oral bioavailability of fisetin was reported 7.8 and 31.7% for oral doses of 100 and 200 mg/kg, respectively
*BBB↑, BBB permeability, fisetin can also affect hippocampal synaptic plasticity indirectly through the peripheral system
*toxicity↑, Furthermore, it did not show signs of toxicity at doses up to 2 g/kg in an acute toxicity study with no toxicity in the histopathological analysis of the heart, lungs, kidneys, liver, stomach, intestines, spleen and reproductive organs
*eff↑, potential benefits against neurological health complications and neurodegenerative diseases like AD, PD. HD, ALS, vascular dementia, schizophrenia, stroke, depression, diabetic neuropathy and traumatic brain injury
*GSH↑, direct antioxidant activity in addition to increasing intracellular antioxidants such as glutathione
*SOD↑, fig 2
*Aβ↓,
*12LOX↓,
*COX2↓,
*Catalase↑, Fisetin treatment prevented behavioral deficits, increased brain antioxidant, superoxide dismutase, catalase, reduced glutathione, and BDNF
*Inflam↓, decreased serum homocysteine, and pro-inflammatory biomarkers (TNF-α, IL-6), lipid peroxidation
*TNF-α↓,
*IL6↑,
*lipid-P↓,
NF-kB↓, suppressed the up-regulation of NF-κB, and IDO-1 genes expression, and decreased the rise of IL-1β levels.
IL1β↓,
NRF2↑, fisetin treatment also restored the downregulation of Nrf-2, HO-1, and ChAT genes expression and BDNF levels in the hippocampus, suggesting its protective effect against oxidative stress
HO-1↑,
GSTs↑, Fisetin also restored the AlCl3-induced reduction in the levels of SOD, CAT, GST, and GSH in a study that analysed the effect of this compound on AlCl3-induced reactive gliosis and neuronal inflammation in the brain of mice
cognitive↑, Fisetin improves neurodegenerative disease-associated dementia, cognitive functions and behavioral abnormalities along with increasing age
*BDNF↑, Fisetin also increases BDNF activity to prevent neurodegeneration

2862- FIS,    Fisetin averts oxidative stress in pancreatic tissues of streptozotocin-induced diabetic rat
- in-vivo, Diabetic, NA
*BG↓, Fisetin treatment showed a significant decline in the levels of blood glucose, glycosylated hemoglobin (HbA1c), NF-kB p65 unit (in pancreas) and IL-1β (plasma), serum nitric oxide (NO) with an elevation in plasma insulin
*NF-kB↓,
*IL1β↓,
*NO↓,
*Insulin↑,
*SOD↑, Furthermore, the levels of activities of enzymatic antioxidants such as SOD, CAT, GPx, and GST were significantly improved in fisetin treated diabetic rats.
*Catalase↑,
*GPx↑,
*GSTs↑,

5392- FIS,  AsP,    Fisetin topical delivery via ascorbyl palmitate/hyaluronan-enhanced limosomes: a novel paradigm for preventing UVB-induced skin photoaging
- in-vivo, Nor, NA
eff↑, Due to FIS’s poor solubility and high lipophilicity, it was encapsulated in D-limonene-modified phospholipid carriers, limosomes (LIMOs), co-formulated with Ascorbyl Palmitate (AP) and Hyaluronan (HYA) to improve FIS’s solubility, skin penetration, a
*antiOx↑, FIS-AP-HYA-LIMOs showed potent in vitro antioxidant activity, high biocompatibility, and remained stable for 6 months.
*MMP9↓, In vivo studies revealed the downregulation of MMP9, TNFα, and NF-κB, accompanied by increased SOD and CAT levels, indicating superior anti-ageing, anti-inflammatory, and antioxidant effects compared to FIS suspension
*TNF-α↓,
*NF-kB↓,
*SOD↑,
*Catalase↑,
*AntiAge↑,
*Inflam↓,
*JNK↓, AP-HYA-LIMOs decreased JNK expression, preserved the integrity of skin layers, and reduced collagen degradation.

1113- FIS,    Fisetin suppresses migration, invasion and stem-cell-like phenotype of human non-small cell lung carcinoma cells via attenuation of epithelial to mesenchymal transition
- in-vitro, Lung, A549 - in-vitro, Lung, H1299
TumCI↓,
TumCMig↓,
EMT↓,
E-cadherin↑, A549
ZO-1↑, h1299
Vim↓,
N-cadherin↓,
MMP2↓,
CD44↓,
CD133↓,
β-catenin/ZEB1↓,
NF-kB↓,
EGFR↓,
STAT3↓,
CSCs↓, ability of fisetin to serve as a potential therapeutic agent on its capacity to attenuate the EMT program and inhibit migration, invasion and stem cell phenotype of lung cancer cells.

2824- FIS,    Fisetin in Cancer: Attributes, Developmental Aspects, and Nanotherapeutics
- Review, Var, NA
*antiOx↑, Fisetin is one such naturally derived flavone that offers numerous pharmacological benefits, i.e., antioxidant, anti-inflammatory, antiangiogenic, and anticancer properties.
*Inflam↓,
angioG↓,
BioAv↓, poor bioavailability associated with its extreme hydrophobicity hampers its clinical utility
BioAv↑, The issues related to fisetin delivery can be addressed by adapting to the developmental aspects of nanomedicines, such as formulating it into lipid or polymer-based systems, including nanocochleates and liposomes
TumCP↓, fisetin also inhibits tumor proliferation by repressing tumor mass multiplication, invasion, migration, and autophagy.
TumCI↓,
TumCMig↓,
*neuroP↑, figure 2
EMT↓, It affects the cell cycle and thereby cell proliferation, microtubule assembly, cell migration and invasion, epithelial to mesenchymal transition (EMT), and cell death
ROS↑, cell death caused by fisetin is possibly due to the induction of apoptosis by fisetin or other signaling molecules and reactive oxygen species (ROS)
selectivity↑, Without influencing the growth of normal cells, fisetin has the capability to hinder the formation of colonies and inhibit the multiplication of cancer cells.
EGFR↓, fisetin restricts the multiplication of EGFR 2-overexpressing SK-BR-3 breast tumor masses
NF-kB↓, fisetin inhibits cancer metastasis by reducing the expressions of nuclear factor-kB (NF-kB)-modulated metastatic proteins in a variety of tumor cell types, including vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP)
VEGF↓,
MMP9↓,
MMP↓, rupturing the plasma membrane, depolarizing mitochondria, cleaving PARP, and activating caspase-7, -8, and -9.
cl‑PARP↑,
Casp7↑,
Casp8↑,
Casp9↑,
*ROS↓, Fisetin is a bioactive flavonol molecule that can easily penetrate the cell membrane due to its hydrophobic nature [51,52], reducing the generation of inflammatory cytokines and reactive oxygen species (ROS) in microglial cells, (normal cells)
uPA↓, Perhaps fisetin lowers angiogenesis, consequently suppressing tumor multiplication by urokinase plasminogen activator (uPA) inhibition
MMP1↓, powerful matrix metalloproteinase (MMP)-1 inhibitor
Wnt↓, Fisetin works on several cellular pathways, such as Wnt, Akt-PI3K, and ERK, as an inhibitor
Akt↓,
PI3K↓,
ERK↓,
Half-Life↝, Fisetin exhibits a very short terminal half-life of approximately 3 hrs in its free form. This half-life is found to be less than that of its metabolites

2825- FIS,    Exploring the molecular targets of dietary flavonoid fisetin in cancer
- Review, Var, NA
*Inflam↓, present in fruits and vegetables such as strawberries, apple, cucumber, persimmon, grape and onion, was shown to possess anti-microbial, anti-inflammatory, anti-oxidant
*antiOx↓, fisetin possesses stronger oxidant inhibitory activity than well-known potent antioxidants like morin and myricetin.
*ERK↑, inducing extracellular signal-regulated kinase1/2 (ERK)/c-myc phosphorylation, nuclear NF-E2-related factor-2 (Nrf2), glutamate cystine ligase and glutathione (GSH) levels
*p‑cMyc↑,
*NRF2↑,
*GSH↑,
*HO-1↑, activate Nrf2 mediated induction of hemeoxygenase-1 (HO-1) important for cell survival
mTOR↓, in our studies on fisetin in non-small lung cancer cells, we found that fisetin acts as a dual inhibitor PI3K/Akt and mTOR pathways
PI3K↓,
Akt↓,
TumCCA↑, fisetin treatment to LNCaP cells resulted in G1-phase arrest accompanied with decrease in cyclins D1, D2 and E and their activating partner CDKs 2, 4 and 6 with induction ofWAF1/p21 and KIP1/p27
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
CDK6↓,
P21↑,
p27↑,
JNK↑, fisetin could inhibit the metastatic ability of PC-3 cells by suppressing of PI3 K/Akt and JNK signaling pathways with subsequent repression of matrix metalloproteinase-2 (MMP-2) and MMP-9
MMP2↓,
MMP9↓,
uPA↓, fisetin suppressed protein and mRNA levels of MMP-2 and urokinase-type plasminogen activator (uPA) in an ERK-dependent fashion.
NF-kB↓, decrease in the nuclear levels of NF-B, c-Fos, and c-Jun was noted in fisetin treated cells
cFos↓,
cJun↓,
E-cadherin↑, upregulation of E-cadherin and down-regulation of vimentin and N-cadherin.
Vim↓,
N-cadherin↓,
EMT↓, EMT inhibiting potential of fisetin has been reported in melanoma cells
MMP↓, The shift in mitochondrial membrane potential was accompanied by release of cytochrome c and Smac/DIABLO resulting in activation of the caspase cascade and cleavage of PARP
Cyt‑c↑,
Diablo↑,
Casp↑,
cl‑PARP↑,
P53↑, fisetin with induction of p53 protein
COX2↓, Fisetin down-regulated COX-2 and reduced the secretion of prostaglandin E2 without affecting COX-1 protein expression.
PGE2↓,
HSP70/HSPA5↓, It was shown that the induction of HSF1 target proteins, such as HSP70, HSP27 and BAG3 were inhibited in HCT-116 cells exposed to heat shock at 43 C for 1 h in the presence of fisetin
HSP27↓,
DNAdam↑, DNA fragmentation, an increase in the number of sub-G1 phase cells, mitochondrial membrane depolarization and activation of caspase-9 and caspase-3.
Casp3↑,
Casp9↑,
ROS↑, This was associated with production of intracellular ROS
AMPK↑, Fisetin induced AMPK signaling
NO↑, fisetin induced cytotoxicity and showed that fisetin induced apoptosis of leukemia cells through generation of NO and elevated Ca2+ activating the caspase
Ca+2↑,
mTORC1↓, Fisetin was shown to inhibit the mTORC1 pathway and its downstream components including p70S6 K, eIF4B and eEF2 K.
p70S6↓,
ROS↓, Others have also noted a similar decrease in ROS with fisetin treatment.
ER Stress↑, Induction of ER stress upon fisetin treatment, evident as early as 6 h, and associated with up-regulation of IRE1, XBP1s, ATF4 and GRP78, was followed by autophagy which was not sustained
IRE1↑,
ATF4↑,
GRP78/BiP↑,
eff↑, Combination of fisetin and the BRAF inhibitor sorafenib was found to be extremely effective in inhibiting the growth of BRAF-mutated human melanoma cells
eff↑, synergistic effect of fisetin and sorafenib was observed in human cervical cancer HeLa cells,
eff↑, Similarly, fisetin in combination with hesperetin induced apoptosis
RadioS↑, pretreatment with fisetin enhanced the radio-sensitivity of p53 mutant HT-29 cancer cells,
ChemoSen↑, potential of fisetin in enhancing cisplatin-induced cytotoxicity in various cancer models
Half-Life↝, intraperitoneal (ip) dose of 223 mg/kg body weight the maximum plasma concentration (2.53 ug/ml) of fisetin was reached at 15 min which started to decline with a first rapid alpha half-life of 0.09 h and a longer half-life of 3.12 h.

2827- FIS,    The Potential Role of Fisetin, a Flavonoid in Cancer Prevention and Treatment
- Review, Var, NA
*antiOx↑, effective antioxidant, anti-inflammatory
*Inflam↓,
neuroP↑, neuro-protective, anti-diabetic, hepato-protective and reno-protective potential.
hepatoP↑,
RenoP↑,
cycD1/CCND1↓, Figure 3
TumCCA↑,
MMPs↓,
VEGF↓,
MAPK↓,
NF-kB↓,
angioG↓,
Beclin-1↑,
LC3s↑,
ATG5↑,
Bcl-2↓,
BAX↑,
Casp↑,
TNF-α↓,
Half-Life↓, Fisetin was given at an effective dosage of 223 mg/kilogram intraperitoneally in mice. The plasma concentration declined biophysically, with a rapid half-life of 0.09 h and a terminal half-life of 3.1 h,
MMP↓, Fisetin powerfully improved apoptotic cells and caused the depolarization of the mitochondrial membrane.
mt-ROS↑, Fisetin played a role in the induction of apoptosis, independently of p53, and increased mitochondrial ROS generation.
cl‑PARP↑, fisetin-induced sub-G1 population as well as PARP cleavage.
CDK2↓, Moreover, the activities of cyclin-dependent kinases (CDK) 2 as well as CDK4 were decreased by fisetin and also inhibited CDK4 activity in a cell-free system, demonstrating that it might directly inhibit the activity of CDK4
CDK4↓,
Cyt‑c↑, Moreover, release of cytochrome c and Smac/Diablo was induced by fisetin
Diablo↑,
DR5↑, Fisetin caused an increase in the protein levels of cleaved caspase-8, DR5, Fas ligand, and TNF-related apoptosis-inducing ligand
Fas↑,
PCNA↓, Fisetin decreased proliferation-related proteins such as PCNA, Ki67 and phosphorylated histone H3 (p-H3) and decreased the expression of cell growth
Ki-67↓,
p‑H3↓,
chemoP↑, Paclitaxel treatment only showed more toxicity to normal cells than the combination of flavonoids with paclitaxel, suggesting that fisetin might bring some safety against paclitaxel-facilitated cytotoxicity.
Ca+2↑, Fisetin encouraged apoptotic cell death via increased ROS and Ca2+, while it increased caspase-8, -9 and -3 activities and reduced the mitochondrial membrane potential in HSC3 cells.
Dose↝, After fisetin treatment at 40 µM, invasion was reduced by 87.2% and 92.4%, whereas after fisetin treatment at 20 µM, invasion was decreased by 52.4% and 59.4% in SiHa and CaSki cells, respectively
CDC25↓, This study proposes that fisetin caused the arrest of the G2/M cell cycle via deactivating Cdc25c as well Cdc2 via the activation of Chk1, 2 and ATM
CDC2↓,
CHK1↑,
Chk2↑,
ATM↑,
PCK1↓, fisetin decreases the levels of SOS-1, pEGFR, GRB2, PKC, Ras, p-p-38, p-ERK1/2, p-JNK, VEGF, FAK, PI3K, RhoA, p-AKT, uPA, NF-ĸB, MMP-7,-9 and -13, whereas it increases GSK3β as well as E-cadherin in U-2 OS
RAS↓,
p‑p38↓,
Rho↓,
uPA↓,
MMP7↓,
MMP13↓,
GSK‐3β↑,
E-cadherin↑,
survivin↓, whereas those of survivin and BCL-2 were reduced in T98G cells
VEGFR2↓, Fisetin inhibited the VEGFR expression in Y79 cells as well as the angiogenesis of a tumor.
IAP2↓, The downregulation of cIAP-2 by fisetin
STAT3↓, fisetin induced apoptosis in TPC-1 cells via the initiation of oxidative damage and enhanced caspases expression by downregulating STAT3 and JAK 1 signaling
JAK1↓,
mTORC1↓, Fisetin acts as a dual inhibitor of mTORC1/2 signaling,
mTORC2↓,
NRF2↑, Moreover, In JC cells, the Nrf2 expression was gradually increased by fisetin from 8 h to 24 h

2828- FIS,    Fisetin, a Potent Anticancer Flavonol Exhibiting Cytotoxic Activity against Neoplastic Malignant Cells and Cancerous Conditions: A Scoping, Comprehensive Review
- Review, Var, NA
*neuroP↑, As a hydrophobic agent, FIS readily penetrates cell membranes and accumulates in cells to exert neuroprotective, neurotrophic and antioxidant effects
*antiOx↑,
*Inflam↓, FIS treatment may include alleviating inflammation, cell apoptosis and oxidative stress
RenoP↑, alleviates cell apoptosis and inflammation in acute kidney injury
COX2↓, FIS induces apoptosis in various tumor cells by, for example, inhibiting cyclooxygenase-2, inhibiting the Wnt/EGFR/NF-κB pathway, activating the caspase-3 cascade
Wnt↓,
EGFR↓,
NF-kB↓,
Casp3↑,
Ca+2↑, activating the caspase-3 and Ca2+ dependent endonuclease, and activating the caspase-8/caspase-3 dependent pathway via ERK1/2.
Casp8↑,
TumCCA↑, FIS controls the cell cycle and inhibits cyclin-dependent kinases (CDKs) in human cancer cell lines,
CDK1↓,
PI3K↓, by inhibition of PI3K/Akt/mTOR signaling [20], mitogen-activated protein kinases (MAPK) [21], and nuclear transcription factor (NF-κB)
Akt↓,
mTOR↓,
MAPK↓,
*P53↓, FIS inhibits aging by reducing p53, p21 and p16 expression in mouse and human tissues
*P21↓,
*p16↓,
mTORC1↓, FIS induces autophagic cell death by inhibiting both the mTORC1 and mTORC2 pathways
mTORC2↓,
P53↑, FIS significantly increases the expression of p53 and p21 proteins and lowers the levels of cyclin D1 [27,28], cyclin A, CDK4 and CDK2, thus contributing to cell-cycle arrest.
P21↑,
cycD1/CCND1↓,
cycA1/CCNA1↓,
CDK2↓,
CDK4↓,
BAX↑, FIS also increases Bax [27,28] and Bak [27] protein expression, but reduces the levels of Bcl-2 [27,28], Bcl-xL [27] and PCNA [28], and then starts the mitochondrial apoptotic pathway.
Bcl-2↓,
PCNA↓,
HER2/EBBR2↓, FIS reduces HER2 tyrosine phosphorylation in a dose-dependent manner and aids in proteasomal degradation of HER2 rather than lysosomal degradation
Cyt‑c↑, FIS cells causes destabilization of the mitochondrial membrane and an increase in cytochrome c levels, which is consistent with the loss of mitochondrial membrane integrity.
MMP↓,
cl‑Casp9↑,
MMP2↓, FIS reduces the enzymatic activity of both MMP-2 and MMP-9.
MMP9↓,
cl‑PARP↑, cell membrane, mitochondrial depolarization, activation of caspase-7, -8 and -9, and cleavage of PARP
uPA↓, interestingly, the promoter activity of the uPA gene is suppressed by FIS
DR4↑, induces upregulation of DR4 and DR5 death receptor expression in a dose-dependent manner
DR5↑,
ROS↓, FIS induces an increase in intracellular Ca2+ but reduces the production of ROS in WEHI-3 cells (myelomonocytic leukemia)
AIF↑, It also increases the levels of caspase-3 and AIF mRNA, but also increases necrosis markers including RIP3 and PARP1
CDC25↓, FIS reduces the expression of cdc25a, but increases the expression of p-p53, Chk1, p21 and p27, which may lead to a G0/G1 arrest.
Dose↑, FIS in concentrations from 0 to 10 μM does not affect cell viability; however, its use at concentrations of 20–40 μM significantly reduces the viability of lung cancer cells
CHOP↑, CaKi : FIS induces upregulation of CHOP expression and ROS production
ROS↑, NCI-H460 :FIS increases the ER stress signaling FIS increases the level of mitochondrial ROS FIS induces mitochondrial Ca2+ overloading and ER stress FIS induced ER stress-mediated cell death via activation of the MAPK pathway
cMyc↓, FIS influences proliferation related genes such as cyclin D1, c-myc and cyclooxygenase (COX)-2 by downregulating them.
cardioP↑, cardioprotective activity

2829- FIS,    Fisetin: An anticancer perspective
- Review, Var, NA
TumCP↓, Being a potent anticancer agent, fisetin has been used to inhibit stages in the cancer cells (proliferation, invasion), prevent cell cycle progression, inhibit cell growth, induce apoptosis, cause polymerase (PARP) cleavage
TumCI↓,
TumCCA↑,
TumCG↓,
Apoptosis↑,
cl‑PARP↑,
PKCδ↓, fisetin also suppresses the activation of the PKCα/ROS/ERK1/2 and p38 MAPK signaling pathways, reduces the NF‐κB activation, and down‐regulates the level of the oncoprotein securin
ROS↓,
ERK↓,
NF-kB↓,
survivin↓,
ROS↑, In human multiple myeloma U266 cells, fisetin stimulated the production of free radical species that led to apoptosis
PI3K↓, Multiple studies also authenticated the anticancer role of fisetin through various signaling pathways such as blocking of mammalian target of rapamycin (PI3K/Akt/mTOR)
Akt↓,
mTOR↓,
MAPK↓, phosphatidylinositol‐3‐kinase/protein kinase B, mitogen‐activated protein kinases (MAPK)‐dependent nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), and p38, respectively,
p38↓,
HER2/EBBR2↓, (HER2)/neu‐overexpressing breast cancer cell lines. Fisetin caused induction through inactivating the receptor, inducing the degradation of the proteasomes, reducing its half‐life
EMT↓, In addition, mutation of epithelial‐to‐mesenchymal transition (EMT)
PTEN↑, up‐regulation of expression of PTEN mRNA and protein were reported after fisetin treatment
HO-1↑, In breast cancer cells (4T1 and JC cells), fisetin increased HO‐1 mRNA and protein expressions, elevated Nrf2 expression
NRF2↑,
MMP2↓, fisetin reduced MMP‐2 and MMP‐9 enzyme activity and gene expression for both mRNA levels and protein
MMP9↓,
MMP↓, fisetin treatment further led to permeabilization of mitochondrial membrane, activation of caspase‐8 and caspase‐9, as well as the cleavage of poly(ADP‐ribose) polymerase 1
Casp8↑,
Casp9↑,
TRAILR↑, enhanced the levels of TRAIL‐R1
Cyt‑c↑, mitochondrial releasing of cytochrome c into cytosol, up‐regulation and down‐regulation of X‐linked inhibitor of apoptosis protein
XIAP↓,
P53↑, fisetin also enhanced the protein p53 levels
CDK2↓, lowered cell number, the activities of CDK‐2,4)
CDK4↓,
CDC25↓, it also decreased cell division cycle protein levels (CDC)2 and CDC25C, and CDC2 activity (Lu et al., 2005)
CDC2↓,
VEGF↓, down‐regulating the expressions of p‐ERK1/2, vascular endothelial growth factor receptor 1(VEGFR1), p38, and pJNK, respectively
DNAdam↑, Fisetin (80 microM) showed dose‐dependently caused DNA fragmentation, induced cellular swelling and apoptotic death, and showed characteristics of apoptosis.
TET1↓, lowered the TET1 expression levels
CHOP↑, caused up‐regulation of (C/EBP) homologous protein (CHOP) expression and reactive oxygen species production,
CD44↓, down‐regulation of CD44 and CD133 markers
CD133↓,
uPA↓, down‐regulation of levels of matrix metalloproteinase‐2 (MMP‐2), urokinase‐type plasminogen activator (uPA),
CSCs↓, Being a potent anticancer agent, fisetin administration in in vitro and in vivo studies in kidney renal stem cells (HuRCSCs) effectively inhibited cancer cell stages such as proliferation,

2830- FIS,    Biological effects and mechanisms of fisetin in cancer: a promising anti-cancer agent
- Review, Var, NA
TumCG↓, suppressing cell growth, triggering programmed cell death, reducing the formation of new blood vessels, protecting against oxidative stress, and inhibiting cell migration.
angioG↓,
*ROS↓,
TumCMig↓,
VEGF↓, including vascular endothelial growth factor (VEGF), mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), PI3K/Akt/mTOR, and Nrf2/HO-1.
MAPK↑, including the activation of MAPK. activation of MAPK is crucial for mediating cancer cell proliferation, apoptosis, and invasion
NF-kB↓, ability of fisetin to suppress NF-κB activity has been demonstrated in various diseases
PI3K↓, fisetin has been shown to inhibit the metastasis of PC3 prostate cancer cells by reducing the activity of the PI3K/AKT
Akt↓,
mTOR↓, Fisetin has been shown to be effective against PI3K expression, AKT phosphorylation, and mTOR activation in various cancer cells,
NRF2↑, effects of fisetin on the activation of Nrf2 and upregulation of HO-1 have been demonstrated in various diseases
HO-1↑,
ROS↓, Liver cancer Resist proliferation, migration and invasion, induce apoptosis, attenuate ROS and inflammation
Inflam↓,
ER Stress↑, Oral cancer Induce apoptosis and autophagy, promote ER stress and ROS, suppress proliferation
ROS↑, Multiple studies have demonstrated that fisetin has the ability to induce apoptosis in cancer cells, and various mechanisms are involved, including the activation of MAPK, NF-κB, p53, and the generation of reactive oxygen species (ROS)
TumCP↓,
ChemoSen↑, Breast cancer Promote apoptosis and invasion and metastasis, enhance chemotherapeutic effects
PTEN↑,
P53↑, activation of MAPK, NF-κB, p53,
Casp3↑,
Casp8↑,
Casp9↑,
COX2↓, fisetin inhibits COX2 expression
Wnt↓, regulating a number of important angiogenesis-related factors in cancer cells, such as VEGF, MMP2/9, eNOS, wingless and Wnt-signaling.
EGFR↓,
Mcl-1↓,
survivin↓, fisetin interferes with NF-κB signaling, resulting in the reduction of survivin, TRAF1, Bcl-xl, Bcl-2, and IAP1/2 levels, ultimately inhibiting apoptosis
IAP1↓,
IAP2↓,
PGE2↓, fisetin inhibits COX2 expression, leading to the down-regulation of PGE2 secretion and inactivation of β-catenin, thereby inducing apoptosis
β-catenin/ZEB1↓,
DR5↑, fisetin markedly induces apoptosis in renal carcinoma through increased expression of DR5, which is regulated by p53.
MMP2↓, fisetin has been shown to inhibit the metastasis of PC3 prostate cancer cells by reducing the activity of the PI3K/AKT and JNK pathways, resulting in the suppression of MMP-2 and MMP-9 expression
MMP9↓,
FAK↓, fisetin can inhibit cell migration and reduce focal adhesion kinase (FAK) phosphorylation levels
uPA↓, fisetin significantly suppresses the invasion of U-2 cells by decreasing the expression of NF-κB, urokinase-type plasminogen activator (uPA), FAK, and MMP-2/9
EMT↓, Fisetin has been shown to have the ability to reverse EMT, thereby inhibiting the invasion and migration of cancer cells
ERK↓, fisetin has the ability to suppress ERK1/2 activation and activate JNK/p38 pathways
JNK↑,
p38↑,
PKCδ↓, fisetin reduces the expression of MMP-9 by inhibiting PKCα/ROS/ERK1/2 and p38 MAPK activation
BioAv↓, low water solubility of fisetin poses a significant challenge for its administration, which can limit its biological effects
BioAv↑, Compared to free fisetin, fisetin nanoemulsion has demonstrated a 3.9-fold increase in the generation of reactive oxygen species (ROS) and induction of apoptosis, highlighting its enhanced efficacy
BioAv↑, Liposomal encapsulation has shown potential in enhancing the anticancer therapeutic effects of fisetin

2832- FIS,    Fisetin's Promising Antitumor Effects: Uncovering Mechanisms and Targeting for Future Therapies
- Review, Var, NA
MMP↓, fraction of cells with reduced mitochondrial membrane potential also increased, indicating that fisetin-induced apoptosis also destroys mitochondria.
mtDam↑,
Cyt‑c↑, Cytochrome c and Smac/DIABLO levels are also released when the mitochondrial membrane potential changes, and this results in the activation of the caspase cascade and the cleavage of poly [ADP-ribose] polymerase (PARP)
Diablo↑,
Casp↑,
cl‑PARP↑,
Bak↑, Fisetin induced apoptosis in HCT-116 human colon cancer cells by upregulating proapoptotic proteins Bak and BIM and downregulating antiapoptotic proteins B cell lymphoma (BCL)-XL and -2.
BIM↑,
Bcl-xL↓,
Bcl-2↓,
P53↑, fisetin through the activation of p53
ROS↑, over generation of ROS, which is also directly initiated by fisetin, the stimulation of AMPK
AMPK↑,
Casp9↑, activating caspase-9 collectively, then activating caspase-3, leading to apopotosis
Casp3↑,
BID↑, Bid, AIF and the increase of the ratio of Bax to Bcl-2, causing the activation of caspase 3–9
AIF↑,
Akt↓, The inhibition of the Akt/mTOR/MAPK/
mTOR↓,
MAPK↓,
Wnt↓, Fisetin has been shown to degrade the Wnt/β/β-catenin signal
β-catenin/ZEB1↓,
TumCCA↑, fisetin triggered G1 phase arrest in LNCaP cells by activating WAF1/p21 and kip1/p27, followed by a reduction in cyclin D1, D2, and E as well as CDKs 2, 4, and 6
P21↑,
p27↑,
cycD1/CCND1↓,
cycE/CCNE↓,
CDK2↓,
CDK4↓,
CDK6↓,
TumMeta↓, reduces PC-3 cells' capacity for metastasis
uPA↓, fisetin decreased MMP-2 protein, messenger RNA (mRNA), and uPA levels through an ERK-dependent route
E-cadherin↑, Fisetin can upregulate the epithelial marker E-cadherin, downregulate the mesenchymal marker vimentin, and drastically lower the EMT regulator twist protein level at noncytotoxic dosages, studies have revealed.
Vim↓,
EMT↓,
Twist↓,
DNAdam↑, Fisetin induces apoptosis in the human nonsmall lung cancer cell line NCI-H460, which causes DNA breakage, the growth of sub-G1 cells, depolarization of the mitochondrial membrane, and activation of caspases 9, 3, which are involved in prod of iROS
ROS↓, fisetin therapy has been linked to a reduction in ROS, according to other research.
COX2↓, Fisetin lowered the expression of COX-1 protein, downregulated COX-2, and decreased PGE2 production
PGE2↓,
HSF1↓, Fisetin is a strong HSF1 inhibitor that blocks HSF1 from binding to the hsp70 gene promoter.
cFos↓, NF-κB, c-Fos, c-Jun, and AP-1 nuclear levels were also lowered by fisetin treatment
cJun↓,
AP-1↓,
Mcl-1↓, inhibition of Bcl-2 and Mcl-1 all contribute to an increase in apoptosis
NF-kB↓, Fisetin's ability to prevent NF-κB activation in LNCaP cells
IRE1↑, fisetin (20–80 µM) was accompanied by brief autophagy and the production of ER stress, which was shown by elevated levels of IRE1 α, XBP1s, ATF4, and GRP78 in A375 and 451Lu cells
ER Stress↑,
ATF4↑,
GRP78/BiP↑,
MMP2↓, lowering MMP-2 and MMP-9 proteins in melanoma cell xenografts
MMP9↓,
TCF-4↓, fisetin therapy reduced levels of β-catenin, TCF-4, cyclin D1, and MMP-7,
MMP7↓,
RadioS↑, fisetin treatment could radiosensitize human colorectal cancer cells that are resistant to radiotherapy.
TOP1↓, fisetin blocks DNA topoisomerases I and II in leukemia cells.
TOP2↓,

2839- FIS,    Dietary flavonoid fisetin for cancer prevention and treatment
- Review, Var, NA
DNAdam↑, Fisetin induced DNA fragmentation, ROS generation, and apoptosis in NCI-H460 cells via a reduction in Bcl-2 and increase in Bax expression
ROS↑,
Apoptosis↑,
Bcl-2↓,
BAX↑,
cl‑Casp9↑, Fisetin treatment increased cleavage of caspase-9 and caspase-3 thereby increasing caspase-3 activation
cl‑Casp3↑,
Cyt‑c↑, leading to cytochrome-c release
lipid-P↓, Fisetin (25 mg/kg body weight) decreased histological lesions and levels of lipid peroxidation and modulated the enzymatic and nonenzymatic anti-oxidants in B(a)P-treated Swiss Albino mice
TumCG↓, We observed that fisetin treatment (5–20 μM) inhibits cell growth and colony formation in A549 NSC lung cancer cells.
TumCA↓, Another study showed that fisetin inhibits adhesion, migration, and invasion in A549 lung cancer cells by downregulating uPA, ERK1/2, and MMP-2
TumCMig↓,
TumCI↓,
uPA↓,
ERK↓,
MMP9↓,
NF-kB↓, Treatment with fisetin also decreased the nuclear levels of NF-kB, c-Fos, c-Jun, and AP-1 and inhibited NF-kB binding.
cFos↓,
cJun↓,
AP-1↓,
TumCCA↑, Our laboratory has previously shown that treatment of LNCaP cells with fisetin caused inhibition of PCa by G1-phase cell cycle arrest
AR↓, inhibited androgen signaling and tumor growth in athymic nude mice
mTORC1↓, induced autophagic cell death in PCa cells through suppression of mTORC1 and mTORC2
mTORC2↓,
TSC2↑, activated the mTOR repressor TSC2, commonly associated with inhibition of Akt and activation of AMPK
EGF↓, Fisetin also inhibits EGF and TGF-β induced YB-1 phosphorylation and EMT in PCa cells
TGF-β↓,
EMT↓, Fisetin also inhibits EGF and TGF-β induced YB-1 phosphorylation and EMT in PCa cells
P-gp↓, decrease the P-gp protein in multidrug resistant NCI/ADR-RES cells.
PI3K↓, Fisetin also inhibited the PI3K/AKT/NFkB signaling
Akt↓,
mTOR↓, Fisetin inhibited melanoma progression in a 3D melanoma skin model with downregulation of mTOR, Akt, and upregulation of TSC
eff↑, combinational treatment study of melatonin and fisetin demonstrated enhanced antitumor activity of fisetin
ROS↓, Fisetin inhibited ROS and augmented NO generation in A375 melanoma cells
ER Stress↑, induction of ER stress evidenced by increased IRE1α, XBP1s, ATF4, and GRP78 levels in A375 and 451Lu cells.
IRE1↑,
ATF4↑,
GRP78/BiP↑,
ChemoSen↑, combination of fisetin with sorafenib effectively inhibited EMT and augmented the anti-metastatic potential of sorafenib by reducing MMP-2 and MMP-9 proteins in melanoma cell xenografts
CDK2↓, Fisetin (0–60 μM) was shown to inhibit activity of CDKs dose-dependently leading to cell cycle arrest in HT-29 human colon cancer cells
CDK4↓, Fisetin treatment decreased activities of CDK2 and CDK4 via decreased levels of cyclin-E, cyclin-D1 and increase in p21 (CIP1/WAF1) levels.
cycE/CCNE↓,
cycD1/CCND1↓,
P21↑,
COX2↓, fisetin (30–120 μM) induces apoptosis in colon cancer cells by inhibiting COX-2 and Wnt/EGFR/NF-kB -signaling pathways
Wnt↓,
EGFR↓,
β-catenin/ZEB1↓, Fisetin treatment inhibited Wnt/EGFR/NF-kB signaling via downregulation of β-catenin, TCF-4, cyclin D1, and MMP-7
TCF-4↓,
MMP7↓,
RadioS↑, fisetin treatment was found to radiosensitize human colorectal cancer cells which are resistant to radiotherapy
eff↑, Combined treatment of fisetin with NAC increased cleaved caspase-3, PARP, reduced mitochondrial membrane potential with induction of caspase-9 in COLO25 cells

2843- FIS,    Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential
- Review, Var, NA
NRF2↑, fisetin increased the protein level and accumulation Nrf2 and down regulated the protein levels of Keap1
Keap1↓,
ChemoSen↑, In vitro studies showed that fisetin and quercetin could also act against chemotherapeutic resistance in several cancers
BioAv↓, Fisetin has low aqueous solubility and bioavailability
Cyt‑c↑, release of cytochrome c from mitochondria, caspase-3 and caspase-9 mRNA and protein expression, and B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X (Bax) levels, were found to be regulated in the fisetin-treated cancer cell line
Casp3↑,
Casp9↑,
BAX↑,
tumCV↓, fisetin at 5–80 µM significantly reduced the viability of A431 human epidermoid carcinoma cells by the release of cytochrome c,
Mcl-1↓, reducing the anti-apoptotic protein expression of Bcl-2, Bcl-xL, and Mcl-1 along with elevation of pro-apoptotic protein expression (Bax, Bak, and Bad) and caspase cleavage and poly-ADP-ribose polymerase (PARP) protein
cl‑PARP↑,
IGF-1↓, fisetin promoted caspase-8 and cytochrome c expression, possibly by impeding the aberrant activation of insulin growth factor receptor 1 and Akt
Akt↓,
CDK6↓, fisetin binds with CDK6, which in turn blocks its activity with an inhibitory concentration (IC50) at a concentration of 0.85 μM
TumCCA↑, fisetin is identified as a regulator of cell cycle checkpoints, leading to cell arrest through CDK inhibition in HL60 cells and astrocyte cells over the G0/G1, S, and G2/M phases
P53?, exhibiting elevated levels of p53
cycD1/CCND1↓, 10–60 μM fisetin concentration, prostate cancer cells PC3, LNCaP, and CWR22Ry1 had decreased cellular viability and decreased levels of D1, D2, and E cyclins and their activating partners CDK2, and CDKs 4/ 6,
cycE/CCNE↓,
CDK2↓, decreased levels of D1, D2, and E cyclins and their activating partners CDK2, and CDKs 4/ 6,
CDK4↓,
CDK6↓,
MMP2↓, fisetin displayed tumor inhibitory effects by blocking MMP-2 and MMP-9 at mRNA and protein levels in prostate PC-3 cells
MMP9↓,
MMP1↓, Similarly, fisetin can also inhibit MMP-1, MMP-9, MMP-7, MMP-3, and MMP-14 gene expression linked with ECM remodeling in human umbilical vascular endothelial cells (HUVECs) and HT-1080 fibrosarcoma cells [9
MMP7↓,
MMP3↓,
VEGF↓, fisetin in a concentration-dependent manner (10–50 μM concentration) significantly inhibited regular serum, growth-enhancing supplement, and vascular endothelial growth factor (VEGF)
PI3K↓, fisetin inhibited PI3K expression and phosphorylation of Akt
mTOR↓, fisetin treatment activated the apoptotic process through inhibiting both PI3K and mammalian target of rapamycin (mTOR) signaling pathways
COX2↓, fisetin resulted in activation of apoptosis and inhibition of COX-2 and the Wnt/EGFR/NF-kB pathway
Wnt↓,
EGFR↓,
NF-kB↓,
ERK↓, Fisetin is one of the flavonoids that has been found to suppress ERK1/2 signaling in human gastric (SGC7901), hepatic (HepG2), colorectal (Caco-2)
ROS↑, fisetin induced ROS generation and suppressed ERK through its phosphorylation
angioG↓, fisetin-induced anti-angiogenesis led to reduced VEGF and epidermal growth factor receptor (EGFR) expression
TNF-α↓, Fisetin suppressed IL-1β-mediated expression of inducible nitric oxide synthase, nitric oxide, interleukin-6, tumor necrotic factor-α, prostaglandin E2, cyclooxygenase-2 (iNOS, NO, IL-6, TNF-α, PGE2, and COX-2),
PGE2↓,
iNOS↓,
NO↓,
IL6↓,
HSP70/HSPA5↝, fisetin-mediated inhibition of cellular proliferation by HSP70 and HSP27 regulation
HSP27↝,

2844- FIS,    Fisetin, a dietary flavonoid induces apoptosis via modulating the MAPK and PI3K/Akt signalling pathways in human osteosarcoma (U-2 OS) cells
- in-vitro, OS, U2OS
tumCV↓, Fisetin at 20-100 µM effectively reduced the viability of OS cells, and induced apoptosis by signifi-cantly inducing the expression of Caspases- 3,-8 and -9 and pro-apoptotic proteins (Bax and Bad) with subsequent down-regulation of Bcl-xL and Bcl-2
Apoptosis↑,
Casp3↑,
Casp8↑,
Casp9↑,
BAX↑,
BAD↑,
Bcl-2↓,
Bcl-xL↓,
PI3K↓, inhibited PI3K/Akt pathway and ERK1/2,
Akt↓,
ERK↓,
p‑JNK↑, it caused enhanced expressions of p-JNK, p-c-Jun and p-p38
p‑cJun↑,
p‑p38↑,
ROS↑, Fisetin-induced ROS generation and decrease in mitochondrial membrane potential
MMP↓, noticeable decline of mitochondrial transmembrane potential (ΔΨm) in a dose-dependent manner
mTORC1↓, fisetin at various concentrations (20-100 μM) caused a significant (p<0.05) decrease in the level of p-Akt and mTORC1 (an important effector protein of Akt), while up-regulated PTEN.
PTEN↑,
p‑GSK‐3β↓, Level of phosphorylated glycogensynthase kinase 3ǃ (GSK3ǃ), (a serine/threonine kinase) and cyclin D1 were potentially decreased by fisetin which is in line with raised non-phosphorylated levels of GSK3ǃ
GSK‐3β↑,
NF-kB↓, Down-regualtion of NF-κB along with significant up-regulations in IκB upon fisetin treatment correlates with the down-regulation of p-Akt levels.
IKKα↑,
Cyt‑c↑, activates the efflux of cytochrome C

3372- QC,  FIS,  KaempF,    Anticancer Potential of Selected Flavonols: Fisetin, Kaempferol, and Quercetin on Head and Neck Cancers
- Review, HNSCC, NA
ROCK1↑, quercetin affects the level of RhoA and NF-κB proteins in SAS cells, and stimulates the expression of RhoA, ROCK1, and NF-κB in SAS cells [53].
TumCCA↓, inhibition of the cell cycle;
HSPs↓, inhibition of heat shock proteins;
RAS↓, inhibition of Ras protein expression.
ROS↑, fisetin induces production of reactive oxygen species (ROS), increases Ca2+ release, and decreases the mitochondrial membrane potential (Ψm) in head and neck neoplastic cells.
Ca+2↑,
MMP↓,
Cyt‑c↑, quercetin increases the expression level of cytochrome c, apoptosis inducing factor and endonuclease G
Endon↑,
MMP9↓, quercetin inhibits MMP-9 and MMP-2 expression and reduces levels of the following proteins: MMP-2, -7, -9 [49,53] and -10
MMP2↓,
MMP7↓,
MMP-10↓,
VEGF↓, as well as VEGF, NF-κB p65, iNOS, COX-2, and uPA, PI3K, IKB-α, IKB-α/β, p-IKKα/β, FAK, SOS1, GRB2, MEKK3 and MEKK7, ERK1/2, p-ERK1/2, JNK1/2, p38, p-p38, c-JUN, and pc-JUN
NF-kB↓,
p65↓,
iNOS↓,
COX2↓,
uPA↓,
PI3K↓,
FAK↓,
MEK↓,
ERK↓,
JNK↓,
p38↓,
cJun↓,
FOXO3↑, Quercetin causes an increase in the level of FOXO1 protein both in a dose- and time-dependent way; however, it does not affect changes in expression of FOXO3a


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 20

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

GSTs↓, 2,   GSTs↑, 1,   GSTs↝, 1,   HO-1↑, 4,   Keap1↓, 1,   lipid-P↓, 1,   NRF2↓, 2,   NRF2↑, 5,   ROS↓, 7,   ROS↑, 13,   mt-ROS↑, 1,  

Mitochondria & Bioenergetics ⓘ

AIF↑, 2,   CDC2↓, 3,   CDC25↓, 4,   EGF↓, 2,   MEK↓, 2,   MMP↓, 11,   mtDam↑, 1,   XIAP↓, 1,  

Core Metabolism/Glycolysis ⓘ

ACC↑, 2,   AMPK↑, 3,   cMyc↓, 1,   PCK1↓, 1,  

Cell Death ⓘ

Akt↓, 11,   Apoptosis↑, 4,   BAD↑, 3,   Bak↑, 1,   BAX↑, 7,   Bcl-2↓, 7,   Bcl-xL↓, 2,   BID↑, 1,   BIM↑, 3,   Casp↑, 3,   Casp3↑, 9,   cl‑Casp3↑, 1,   Casp7↑, 2,   Casp8↑, 6,   cl‑Casp8↑, 1,   Casp9↑, 7,   cl‑Casp9↑, 2,   Chk2↑, 1,   Cyt‑c↑, 12,   Diablo↑, 5,   DR4↑, 1,   DR5↑, 5,   Endon↑, 1,   Fas↑, 3,   IAP1↓, 1,   IAP2↓, 2,   iNOS↓, 2,   JNK↓, 1,   JNK↑, 2,   p‑JNK↑, 1,   MAPK↓, 4,   MAPK↑, 1,   Mcl-1↓, 5,   MDM2↓, 1,   Myc↓, 1,   p27↑, 2,   p38↓, 4,   p38↑, 1,   p‑p38↓, 1,   p‑p38↑, 1,   survivin↓, 3,   TRAIL↑, 2,   TRAILR↑, 1,  

Kinase & Signal Transduction ⓘ

HER2/EBBR2↓, 2,   p70S6↓, 1,   TSC2↑, 1,  

Transcription & Epigenetics ⓘ

cJun↓, 6,   p‑cJun↑, 1,   p‑H3↓, 1,   other↝, 1,   tumCV↓, 2,  

Protein Folding & ER Stress ⓘ

CHOP↑, 3,   ER Stress↑, 4,   GRP78/BiP↑, 3,   HSF1↓, 1,   HSP27↓, 2,   HSP27↝, 1,   HSP70/HSPA5↓, 3,   HSP70/HSPA5↝, 1,   HSPs↓, 1,   IRE1↑, 3,  

Autophagy & Lysosomes ⓘ

ATG5↑, 1,   Beclin-1↑, 1,   LC3s↑, 1,  

DNA Damage & Repair ⓘ

ATM↑, 1,   CHK1↑, 1,   DNAdam↑, 6,   P53?, 1,   P53↑, 8,   cl‑PARP↑, 9,   PCNA↓, 2,  

Cell Cycle & Senescence ⓘ

CDK1↓, 1,   CDK2↓, 10,   CDK4↓, 10,   cycA1/CCNA1↓, 2,   cycD1/CCND1↓, 8,   cycE/CCNE↓, 5,   P21↑, 7,   p‑RB1↓, 1,   Securin↓, 1,   TumCCA↓, 1,   TumCCA↑, 9,  

Proliferation, Differentiation & Cell State ⓘ

CD133↓, 2,   CD44↓, 2,   cFos↓, 5,   CSCs↓, 2,   EMT↓, 8,   ERK↓, 7,   ERK↑, 1,   p‑ERK↓, 1,   FOXO3↑, 1,   GSK‐3β↑, 2,   p‑GSK‐3β↓, 1,   IGF-1↓, 1,   mTOR↓, 9,   mTORC1↓, 5,   mTORC2↓, 3,   PI3K↓, 10,   PTEN↑, 3,   RAS↓, 2,   STAT3↓, 2,   TCF↑, 1,   TCF-4↓, 2,   TOP1↓, 1,   TOP2↓, 1,   TumCG↓, 4,   Wnt↓, 10,  

Migration ⓘ

AP-1↓, 2,   Ca+2↑, 4,   E-cadherin↓, 1,   E-cadherin↑, 5,   FAK↓, 2,   Fibronectin↓, 2,   Ki-67↓, 1,   MET↓, 1,   MMP-10↓, 1,   MMP1↓, 3,   MMP13↓, 1,   MMP2↓, 10,   MMP3↓, 2,   MMP7↓, 6,   MMP9↓, 11,   MMPs↓, 1,   N-cadherin↓, 4,   PKCδ↓, 3,   Rho↓, 1,   ROCK1↑, 1,   Snail↓, 2,   TET1↓, 1,   TGF-β↓, 1,   TumCA↓, 1,   TumCI↓, 5,   TumCMig↓, 4,   TumCP↓, 3,   TumMeta↓, 2,   Twist↓, 2,   uPA↓, 11,   Vim↓, 5,   Zeb1↓, 1,   ZO-1↑, 1,   β-catenin/ZEB1↓, 6,  

Angiogenesis & Vasculature ⓘ

angioG↓, 5,   ATF4↓, 1,   ATF4↑, 3,   EGFR↓, 10,   eNOS↓, 1,   NO↓, 1,   NO↑, 1,   VEGF↓, 7,   VEGFR2↓, 1,  

Barriers & Transport ⓘ

P-gp↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 11,   IKKα↑, 1,   IL1β↓, 1,   IL6↓, 1,   Inflam↓, 2,   JAK1↓, 1,   NF-kB↓, 18,   NF-kB↑, 1,   p65↓, 2,   PGE2↓, 6,   TNF-α↓, 2,  

Hormonal & Nuclear Receptors ⓘ

AR↓, 1,   CDK6↓, 4,  

Drug Metabolism & Resistance ⓘ

BioAv↓, 3,   BioAv↑, 3,   BioAv↝, 1,   ChemoSen↑, 7,   Dose↑, 1,   Dose↝, 1,   eff↑, 8,   Half-Life↓, 1,   Half-Life↝, 2,   P450↓, 1,   P450↝, 1,   RadioS↑, 4,   selectivity↑, 2,  

Clinical Biomarkers ⓘ

AR↓, 1,   EGFR↓, 10,   HER2/EBBR2↓, 2,   IL6↓, 1,   Ki-67↓, 1,   Myc↓, 1,  

Functional Outcomes ⓘ

cardioP↑, 1,   chemoP↑, 1,   cognitive↑, 1,   hepatoP↑, 1,   neuroP↑, 1,   RenoP↑, 2,   Risk↓, 1,  
Total Targets: 213

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↓, 1,   antiOx↑, 6,   Catalase↑, 3,   GPx↑, 1,   GSH↑, 2,   GSTs↑, 1,   HO-1↑, 1,   lipid-P↓, 1,   NRF2↑, 2,   ROS↓, 3,   SOD↑, 3,  

Mitochondria & Bioenergetics ⓘ

Insulin↑, 1,  

Core Metabolism/Glycolysis ⓘ

12LOX↓, 1,   p‑cMyc↑, 1,  

Cell Death ⓘ

JNK↓, 1,  

DNA Damage & Repair ⓘ

p16↓, 1,   P53↓, 1,  

Cell Cycle & Senescence ⓘ

P21↓, 1,  

Proliferation, Differentiation & Cell State ⓘ

ERK↑, 1,  

Migration ⓘ

MMP9↓, 1,  

Angiogenesis & Vasculature ⓘ

NO↓, 1,   NO↑, 1,  

Barriers & Transport ⓘ

BBB↑, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 1,   IL1β↓, 1,   IL6↑, 1,   Inflam↓, 6,   NF-kB↓, 2,   TNF-α↓, 2,  

Synaptic & Neurotransmission ⓘ

BDNF↑, 1,  

Protein Aggregation ⓘ

Aβ↓, 1,  

Drug Metabolism & Resistance ⓘ

eff↑, 1,  

Clinical Biomarkers ⓘ

BG↓, 1,   IL6↑, 1,  

Functional Outcomes ⓘ

AntiAge↑, 1,   neuroP↑, 4,   toxicity↑, 1,  
Total Targets: 37

Scientific Paper Hit Count for: NF-kB, Nuclear factor kappa B
20 Fisetin
1 Ascorbyl Palmitate
1 Quercetin
1 Kaempferol
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#:78  Target#:214  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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