Ion Channel-Targeting Modulators in Glioma: Pharmacological Advances and Therapeutic Perspectives

Highly aggressive gliomas remain difficult to treat because of their marked invasiveness, frequent recurrence, and association with glioma-related epilepsy. Increasing evidence suggests that ion channels expressed in glioma cells, including voltage-gated Na⁺ channels, large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels, intermediate-conductance Ca²⁺-activated K⁺ (IK_Ca) channels, and inwardly rectifying K⁺ (Kir) channels, contribute to these malignant phenotypes and represent potential therapeutic targets. This perspective summarizes current evidence for eight representative drugs and phytoconstituents-perampanel, valproic acid, cilostazol, berberine, oxaliplatin, temozolomide, arecoline, and triptolide-that modulate these ion channels. Perampanel and valproic acid suppress voltage-gated Na⁺ current in glioma cells and may provide additional benefits in controlling glioma-associated epilepsy. Cilostazol activates BK_Ca channels, whereas berberine, oxaliplatin, and temozolomide inhibit IK_Ca channel activity. Arecoline suppresses IK_Ca and Kir channel activity, while triptolide inhibits Kir channels. These observations suggest that ion channel modulation may influence glioma cell proliferation, migration, invasion, and excitability. To complement the available experimental evidence, we performed molecular docking analyses as a hypothesis-generating approach to explore potential ligand-channel interactions. Because these computational predictions have not been experimentally validated, they should be interpreted cautiously and viewed as a framework for future mechanistic studies rather than definitive evidence of binding. We also discuss important translational considerations, including the limited clinical evidence and the toxicity profiles of several compounds. In particular, arecoline is associated with carcinogenicity and neurotoxicity, triptolide with significant systemic toxicity, berberine with poor oral bioavailability and potential drug interactions, and oxaliplatin with dose-limiting neurotoxicity. Overall, this perspective highlights ion channels as promising therapeutic targets in glioma while emphasizing the need for rigorous experimental validation and careful evaluation of safety before clinical translation.