Database Query Results : Fisetin, , TumMeta

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↓, 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


TumMeta, Cancer Metastasis: Click to Expand ⟱
Source:
Type:
Cancer metastasis is the process by which cancer cells spread from the original (primary) tumor to other parts of the body, forming new (secondary) tumors. This occurs when cancer cells invade surrounding tissues, enter the bloodstream or lymphatic system, and travel to distant organs or tissues.


Scientific Papers found: Click to Expand⟱
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

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↓,


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 2

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

GSTs↓, 1,   HO-1↑, 1,   NRF2↓, 1,   ROS↓, 1,   ROS↑, 2,  

Mitochondria & Bioenergetics ⓘ

AIF↑, 1,   EGF↓, 1,   MMP↓, 2,   mtDam↑, 1,  

Core Metabolism/Glycolysis ⓘ

ACC↑, 1,   AMPK↑, 2,  

Cell Death ⓘ

Akt↓, 2,   BAD↑, 1,   Bak↑, 1,   BAX↑, 1,   Bcl-2↓, 2,   Bcl-xL↓, 1,   BID↑, 1,   BIM↑, 2,   Casp↑, 1,   Casp3↑, 2,   Casp9↑, 1,   Cyt‑c↑, 2,   Diablo↑, 2,   MAPK↓, 1,   Mcl-1↓, 2,   Myc↓, 1,   p27↑, 1,   p38↓, 1,  

Transcription & Epigenetics ⓘ

cJun↓, 2,  

Protein Folding & ER Stress ⓘ

ER Stress↑, 1,   GRP78/BiP↑, 1,   HSF1↓, 1,   HSP27↓, 1,   HSP70/HSPA5↓, 1,   IRE1↑, 1,  

DNA Damage & Repair ⓘ

DNAdam↑, 2,   P53↑, 2,   cl‑PARP↑, 2,  

Cell Cycle & Senescence ⓘ

CDK2↓, 2,   CDK4↓, 2,   cycA1/CCNA1↓, 1,   cycD1/CCND1↓, 2,   cycE/CCNE↓, 1,   P21↑, 2,   TumCCA↑, 2,  

Proliferation, Differentiation & Cell State ⓘ

cFos↓, 2,   EMT↓, 2,   mTOR↓, 2,   PI3K↓, 1,   TCF-4↓, 1,   TOP1↓, 1,   TOP2↓, 1,   Wnt↓, 2,  

Migration ⓘ

AP-1↓, 1,   E-cadherin↑, 2,   Fibronectin↓, 1,   MET↓, 1,   MMP1↓, 1,   MMP2↓, 2,   MMP3↓, 1,   MMP7↓, 2,   MMP9↓, 2,   N-cadherin↓, 1,   Snail↓, 1,   TumMeta↓, 2,   Twist↓, 2,   uPA↓, 2,   Vim↓, 2,   Zeb1↓, 1,   β-catenin/ZEB1↓, 1,  

Angiogenesis & Vasculature ⓘ

angioG↓, 1,   ATF4↓, 1,   ATF4↑, 1,   EGFR↓, 1,   eNOS↓, 1,   VEGF↓, 1,  

Immune & Inflammatory Signaling ⓘ

COX2↓, 2,   NF-kB↓, 2,   p65↓, 1,   PGE2↓, 1,  

Hormonal & Nuclear Receptors ⓘ

CDK6↓, 1,  

Drug Metabolism & Resistance ⓘ

ChemoSen↑, 1,   eff↑, 1,   RadioS↑, 1,  

Clinical Biomarkers ⓘ

EGFR↓, 1,   Myc↓, 1,  
Total Targets: 87

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 1,   NRF2↑, 1,  

Functional Outcomes ⓘ

neuroP↑, 1,  
Total Targets: 3

Scientific Paper Hit Count for: TumMeta, Cancer Metastasis
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#:604  State#:%  Dir#:%
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