Isoflavones as multi-target modulators in glioma and neuroblastoma: a mini-review

Brain tumors, including gliomas and neuroblastoma (NB), remain among the most aggressive and therapeutically challenging malignancies of the nervous system. Despite multimodal treatment, prognosis for high-grade gliomas and high-risk NB remains poor, largely due to pharmacological barriers and intrinsic therapy resistance. Isoflavones are plant-derived phytoestrogens that have attracted increasing attention because of their pleiotropic anticancer, anti-inflammatory, and neuroprotective properties. In this review, we focus on the molecular and cellular mechanisms that determine the biological activity of isoflavones in brain tumors, including estrogen receptor-dependent signaling, modulation of oncogenic pathways, and limitations related to blood-brain barrier permeability. We discuss how modulation of phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK), and nuclear factor kappa B (NF-κB) pathways contributes to antiproliferative and pro-apoptotic effects, and how limited brain bioavailability represents a major barrier to effective application. We identify key limitations of the current literature, including inconsistent epidemiological findings, poor standardization of experimental models, and limited pharmacokinetic characterization. Available data suggest that isoflavones represent promising adjuncts in brain tumor therapy, but their clinical relevance will depend on improving brain delivery and defining receptor-selective mechanisms of action.