FIS mechanism of action and biological effects.
| Mechanism | FIS’s action | Biological effect | Tumor types affected | Reference |
|---|---|---|---|---|
| Cell cycle modulation | Induces G1/S arrest | Modifies cell cycle distribution | Glioblastoma (U-138 MG) | [45] |
| Apoptosis induction | Activates caspases-3, -8, and -9 | Increases apoptosis in glioblastoma cells | ||
| Nanoparticle encapsulation | Encapsulated in PLGA nanoparticles (FIS-PLGA-NP4) | Enhances stability and drug loading, cytotoxicity improvement | ||
| Radiostability | Exposure to ionizing radiation (25 kGy) | Maintains structural integrity, suitable for sterilization | ||
| Combination therapy | Synergistic effect with chemotherapeutics | Enhances efficacy and reduces resistance | ||
| DNA damage | Induces DNA strand breaks, measured by alkaline comet and γH2AX assay | Initiates genotoxicity and the DNA damage response via p53 signaling | Glioblastoma | [46] |
| Apoptosis induction | Induces apoptosis through flow cytometry analysis | Increases cell death through apoptosis, thereby lowering overall cell survival | ||
| Senescence reduction | Reduces senescence induced by TMZ | Decreases the number of senescent cells, thereby increasing apoptosis | ||
| DNA repair inhibition | Inhibits DNA repair pathways such as BER | Increases DNA damage, thereby increasing cell death | ||
| Enhancement of chemotherapy | Enhances the genotoxic effect of TMZ | Increases the efficiency of temozolomide by enhancing cell death and inhibiting senescence | ||
| Cell proliferation inhibition | Inhibits cell proliferation in T98G cells | Inhibits cell viability and growth in MTT assays as indicated by a lower IC50 in T98G cells | Glioblastoma (T98G cells) | [47] |
| Apoptosis activation | Induces apoptosis in T98G cells via caspases 3, 8, 9, and Bax | Enhances apoptotic indices by assessing caspase activation, mitochondrial destabilisation, and DNA fragmentation | ||
| Cytotoxicity comparison | More cytotoxic in T98G cells than carmustine (positive control) | Causes cell death and cytotoxicity at lower concentrations in T98G cells than carmustine | ||
| Gene expression modulation | Increases CASPASE-3, CASPASE-9, BAX, and decreases BCL-2 | Regulates the expression of genes involved in apoptosis, thereby promoting apoptosis | ||
| Cell migration inhibition | Suppresses glioma cell migration at non-cytotoxic concentrations | Reduces the migration and motility ability of malignant cells | Glioma (GBM8401 cells) | [48] |
| Cell invasion suppression | Inhibits invasion through the extracellular matrix | Inhibits the limits of the invasion potential without causing cytotoxicity | ||
| ADAM9 downregulation | Decreases ADAM9 protein and mRNA expression | Insulates glioma development and invasion-related proteins | ||
| ERK1/2 signaling modulation | Induces sustained phosphorylation of ERK1/2 | ERK1/2 is activated, leading to the inhibition of the ADAM9 expression | ||
| ERK1/2-dependent anti-invasive effect | ERK1/2 inhibition (U0126 or siERK) reverses FIS’s effects | Elevates the ERK1/2 as a requisite mediator of the anti-invasive effect of FIS | ||
| Tumor microenvironment modulation | Alters the tumor microenvironment, affects autophagy and apoptosis pathways | Enhances a better treatment response and reduces treatment resistance | Glioblastoma, glioma | [49] |
| Active targeting | Modification with cRGD peptide | Penetrates the blood-brain barrier to reach glioma cells | Glioblastoma, glioma GL261 or U87-MG cells | [56] |
| Redox-responsive release | Disulfide bond-containing nanoparticles | Breaks down under the condition of increased glutathione, thus, liberating FIS and doxorubicin | ||
| Enhancement of drug uptake | FIS inhibits P-glycoprotein (P-gp) | Modifies the cellular localization of doxorubicin and other chemotherapeutic agents | ||
| Cell cycle arrest | Induction of G2/M phase arrest | Prevents the multiplication and movement of glioma cells | ||
| Apoptosis promotion | Activation of the caspase cascade | Causes oligonucleotide apoptosis via exogenous and endogenous mechanisms | ||
| Synergistic effects with DOX | Combination with DOX-loaded nanoparticles | A synergistic increase in tumor suppression and a decrease in drug resistance | ||
| Cell proliferation | Decreases cell proliferation in both TMZ-sensitive and TMZ-resistant cells | Reduced cell viability and growth inhibition | Glioblastoma (TMZ-resistant T98G23 and TMZ-sensitive A172 cells) | [57] |
| Cell migration | Inhibits migration in TMZ-treated GB cells, enhancing the effects of TMZ | Suppression of the migratory behavior of glioblastoma cells | ||
| Combination therapy | TMZ + FIS combination treatment | Enhanced chemotherapeutic efficacy, overcoming resistance in glioblastoma models | ||
| PI3K/Akt/CREB pathway | Activates PI3K/Akt/CREB signaling | Promotes neuronal survival and neuroprotection | Neurodegenerative disorders | [58] |
FIS: fisetin; PLGA: poly(lactic-co-glycolic acid); NP: nanoparticle; γH2AX: gamma H2A histone family member X; TMZ: temozolomide; IC50: half-maximal inhibitory concentration; ADAM9: A disintegrin and metalloproteinase 9; ERK: extracellular signal-regulated kinase; BER: base excision repair; MTT: methylthiazolyldiphenyl-tetrazolium bromide; cRGD: cyclic arginine-glycine-aspartic acid (peptide); DOX: doxorubicin; PI3K: phosphatidylinositol 3-kinase; Akt: protein kinase B; mTOR: mechanistic (mammalian) target of rapamycin. CREB: cAMP response element-binding protein.