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| 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 — a naturally occurring plant flavonol and polyphenolic bioactive compound, chemically identified as 3,3′,4′,7-tetrahydroxyflavone. It is classified as a dietary flavonoid, experimental senotherapeutic and preclinical anticancer agent; Fisetin occurs in strawberries, apples, persimmons, grapes, onions and cucumbers, with strawberries providing one of the higher concentrations among commonly consumed foods. Its reported anticancer, neuroprotective and senolytic actions remain predominantly preclinical, and it is not an approved cancer or Alzheimer’s disease therapy. Primary mechanisms (ranked):
Bioavailability / PK relevance: Native fisetin has very low aqueous solubility, rapid intestinal and hepatic conjugation, and limited systemic exposure to unconjugated fisetin after conventional oral administration. Glucuronide, sulfate and methylated metabolites can predominate in circulation. Human PK evidence remains limited, although formulated preparations can produce substantially greater exposure than unformulated fisetin. Liposomal, nanoemulsion, phospholipid, cyclodextrin and other delivery systems are therefore mechanistically relevant but cannot be assumed equivalent to ordinary supplements. In-vitro vs systemic exposure relevance: Many anticancer experiments use approximately 10–100 µM fisetin, commonly 20–80 µM. These concentrations are substantially above the free-parent concentrations expected after ordinary dietary intake and may exceed those produced by conventional oral supplements. Direct translation of cytotoxic concentrations is therefore poor unless tumor accumulation, active metabolites or an exposure-enhancing formulation is demonstrated. Clinical evidence status: Cancer evidence is predominantly cell-culture and animal evidence. Early human studies are evaluating fisetin as a senolytic or supportive intervention in aging, frailty and cancer-survivor populations, but there is no completed randomized evidence establishing antitumor efficacy. Fisetin should be categorized as preclinical for direct cancer treatment and investigational for adjunct or senotherapeutic use. Safety / interaction constraints: Food-level exposure is generally regarded as low risk, and small short-term human studies have not identified a clear severe toxicity signal. However, high intermittent senolytic dosing and long-term supplemental dosing remain insufficiently characterized. Mechanistic concerns include antiplatelet or anticoagulant additivity, modulation of drug-metabolizing enzymes and transporters, topoisomerase inhibition, and context-dependent interference with oxidative or cytotoxic cancer treatments. Product purity and formulation-dependent exposure are additional uncertainties. Fisetin Mechanistic Ranking
P: 0–30 min R: 30 min–3 hr G: >3 hr Alzheimer’s disease relevance: Fisetin has significant but predominantly preclinical relevance to Alzheimer’s disease and related neurodegenerative disorders. Experimental studies report preservation of synaptic function and cognition, suppression of microglial inflammatory signaling, reduction of oxidative stress, promotion of autophagic clearance of phosphorylated tau, and modulation of amyloid-associated toxicity. Senescent-cell clearance provides an additional emerging rationale, but the relative contribution of senolysis versus direct neuroprotective signaling is unresolved. A pilot clinical study in mild cognitive impairment or mild Alzheimer’s disease is registered, but no completed trial currently establishes cognitive efficacy. Exposure constraint: Most neurological evidence comes from cell and animal models. Native fisetin’s poor solubility, rapid conjugation and uncertain free-brain exposure materially limit direct translation. CMS121 and other fisetin-derived compounds are being developed partly to improve potency, metabolic stability and neuroprotective exposure. Fisetin in Alzheimer’s Disease
P: 0–30 min R: 30 min–3 hr G: >3 hr |
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| Once the cancer has begun, NO seems to play a protumoral role rather than antitumoral one as the concentration required to cause tumor cell cytotoxicity cannot be achieved by cancer cells. The mechanistic roles of nitric oxide (NO) during cancer progression have been important considerations since its discovery as an endogenously generated free radical. Nonetheless, the impacts of this signaling molecule can be seemingly contradictory, being both pro-and antitumorigenic, which complicates the development of cancer treatments based on the modulation of NO fluxes in tumors. At a fundamental level, low levels of NO drive oncogenic pathways, immunosuppression, metastasis, and angiogenesis, while higher levels lead to apoptosis and reduced hypoxia and also sensitize tumors to conventional therapies. However, clinical outcome depends on the type and stage of the tumor as well as the tumor microenvironment. Nitric oxide is generated by three main nitric oxide synthase isoforms: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). – In many cancers, especially under inflammatory conditions, iNOS expression is upregulated. In contrast, eNOS levels may also be altered in cancers such as breast or prostate cancer. • Expression Patterns in Tumors: – Elevated iNOS expression is commonly observed in various tumor types (e.g., colon, breast, lung, and melanoma) and is often associated with an inflammatory microenvironment. – Changes in eNOS and nNOS expression have also been reported and may contribute to angiogenesis and tumor blood flow regulation. |
| 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 |
| 2825- | FIS, | Exploring the molecular targets of dietary flavonoid fisetin in cancer |
| - | Review, | Var, | NA |
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
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