Fisetin

Fisetin: Nature's Promising Anticancer Flavonoid

A powerful flavonoid from strawberries with multi-targeted cancer-fighting mechanisms

Key Research Findings

• Multi-Target Approach: Inhibits PI3K/Akt/mTOR, NF-κB, and MAPK pathways simultaneously
• Apoptosis Induction: Triggers cancer cell death via mitochondrial and death receptor pathways
• EMT Inhibition: Suppresses epithelial-mesenchymal transition and metastasis
• Synergistic Effects: Preclinical studies show potential for synergistic mechanisms.

What is Fisetin?

Fisetin is a natural flavonoid abundant in strawberries, apples, cucumbers, and other plant-based foods. This bioactive compound has emerged as one of the most promising natural substances for cancer therapy, demonstrating significant potential through multi-targeted anti-cancer mechanisms and synergistic effects when combined with conventional treatments.

Natural Sources

Strawberries are the richest dietary source of fisetin, containing up to 160 μg/g fresh weight. Other significant sources include apples, persimmons, grapes, onions, and cucumbers. The compound gives many fruits their vibrant colors and provides natural protection against oxidative stress.

Core Anti-Cancer Mechanisms

Signaling Pathway Regulation

Fisetin inhibits key pathways such as PI3K/Akt/mTOR, NF-κB, and MAPK, effectively blocking cancer cell proliferation, survival, and metastasis. In cervical cancer HeLa cells, studies show fisetin reduces Akt phosphorylation, suppresses mTOR signaling, and inhibits NF-κB nuclear translocation, thereby decreasing pro-inflammatory cytokines and anti-apoptotic proteins.

Apoptosis Induction Mechanisms

Fisetin triggers apoptosis via mitochondrial pathways including mitochondrial membrane potential collapse and cytochrome c release, as well as death receptor pathways through DR5-mediated caspase-8/caspase-3 cascade activation.

When combined with sorafenib in HeLa cells, fisetin enhances the Bax/Bcl-2 ratio, activates caspase-3, and promotes PARP cleavage, significantly accelerating apoptosis.

EMT and Metastasis Inhibition

Fisetin downregulates epithelial-mesenchymal transition (EMT) markers including β-catenin, Snail, and Twist, while also suppressing mesenchymal markers such as N-cadherin and vimentin. This dual action effectively suppresses melanoma invasion and metastasis, making it particularly valuable for preventing cancer spread.

Cellular Protection Mechanisms

• ROS Scavenging: Neutralizes reactive oxygen species while selectively targeting cancer cells
• Enzyme Activation: Stimulates antioxidant enzymes including SOD and catalase
• Inflammation Reduction: Inhibits NF-κB and reduces pro-inflammatory cytokines (IL-6, TNF-α)
• Microenvironment Modulation: Improves tumor microenvironment conditions

Dosage & Bioavailability

Current Research Dosages

Animal Models: 50-200 mg/kg body weight showed optimal therapeutic effects

Human Equivalent: 100-200 mg/day based on preclinical extrapolation

Bioavailability Challenge: Oral bioavailability is relatively low at 10-20%, requiring advanced delivery systems

Delivery System Innovations

• Liposomal Formulations: Improve bioavailability and targeted delivery
• Polymeric Micelles: Enhanced cellular uptake and stability
• Prodrug Modifications: Chemical modifications to improve absorption
• Nanotechnology Applications: Precision targeting of tumor tissues

Safety Considerations

General Safety: Preclinical studies confirm safety within research dosage ranges (50-200 mg/kg)

Side Effects: High doses may cause gastrointestinal discomfort in some individuals

Drug Interactions: Potential interactions with cytochrome P450 enzyme systems

Medical Supervision: Consultation with healthcare providers recommended, especially during cancer treatment

Research Status & Clinical Evidence

Preclinical Foundation: Extensive in vitro and animal studies demonstrate consistent anticancer activity across multiple cancer types

Mechanistic Understanding: Well-characterized molecular pathways and synergistic mechanisms with conventional therapies

Clinical Translation: Human clinical trials are needed to validate preclinical findings and establish optimal dosing protocols

Combination Therapy Promise: Strong preclinical evidence supports development of fisetin-based combination treatments

Scientific References & Evidence

Synergistic Combination Studies

Fisetin + Sorafenib: Laboratory evidence in cervical cancer HeLa cells showing synergistic apoptosis induction via DR5/caspase-8/mitochondrial pathways. Mouse xenograft studies demonstrate superior tumor inhibition compared to single agents (MDPI journal Nutrients 2023 review. PMID: 26662956).

Fisetin + Platinum/Taxanes: Mechanistic insights showing enhanced chemosensitivity through P-glycoprotein reduction and increased intracellular drug concentration. Efficacy demonstrated in lung/ovarian cancer models (ScienceDirect 2025 study).

Fisetin + PI3K/mTOR Inhibitors: Pathway modulation studies showing Akt/mTOR signaling suppression, amplifying effects of rapamycin or PI3K inhibitors in breast/renal cancer models. Enhanced tumor suppression observed with fisetin + everolimus. (PMID: 29749427).

Fisetin + EGFR/VEGF Inhibitors: Kim N, Kwon J, Shin US, Jung J. Fisetin induces the upregulation of AKAP12 mRNA and anti-angiogenesis in a patient-derived organoid xenograft model. Biomed Pharmacother. 2023 Nov;167:115613. doi: 10.1016/j.biopha.2023.115613. Epub 2023 Oct 4. PMID: 37801904.

Fisetin + PD-1/PD-L1 Inhibitors: Fisetin, as a senotherapeutic, may enhance PD-1 inhibitor efficacy by reducing immunosenescence. Liu, N., Wu, J., Deng, E. et al. Immunotherapy and senolytics in head and neck squamous cell carcinoma: phase 2 trial results. Nat Med (2025). https://doi.org/10.1038/s41591-025-03873-7

Research Limitations

Current evidence is primarily preclinical (laboratory and animal studies). Large-scale clinical trials validating synergistic effects and establishing optimal human dosing protocols are needed. Bioavailability challenges require advanced delivery system development.

Medical Disclaimer: This information is for educational purposes only and should not replace professional medical advice. Fisetin should not be used as a substitute for conventional cancer treatments. All anticancer evidence is preclinical - human clinical trials are needed to establish safety and efficacy. Always consult healthcare providers before use, especially during cancer treatment or when taking medications.

Last updated: September 2025