Dual Targeting of Brain Tumors and Their Environment by Bumetanide and Mebendazole

Background: The anti-epileptic NKCC1 inhibitor Bumetanide (BUM) and the microtubule acting anthelminthic agent Mebendazole (MEB), have anti-cancer properties. Tumor & its environment generate neuronal hyperactivity that aggravates the clinical outcome suggesting that their combination might block hyperactivity (BUM) and augment cell death (MEB). Methods: We tested the effects of the combo on i) NKCC1 activity in human cell lines, ii) electrical activity recorded from mouse hippocampal neurons & tumors freshly resected from patients, iii) glioblastoma-brain co-cultures, iv) cell death in human tumoroids. Results: BUM efficiently inhibited NKCC1 & unexpectedly, MEB applications also via a likely indirect action. In rodent hippocampal neurons, BUM blocked GABAergic Giant Depolarizing Potentials and seizures and co-applications of MEB produced a fourfold increase of BUM's efficacy. In freshly removed brain tumors, E GABA reversal recorded with single GABA channels was highly depolarized (close to -25 mV) in keeping with NKCC1 over activity. BUM fully blocked ongoing epileptic activity. In GBM-Brain cultures, the combo produced stronger effects then independent applications of MEB or BUM. In tumoroids, the combo also efficiently produced strong cell death & morphological changes in some tumors. Conclusion: The combination of BUM & MEB acts complementarily on brain tumors, the former blocking seizures, and the latter producing cell death. Their combination increases their hyperactivity inhibitory actions and cell death. The combo might therefore be used to treat brain tumors combining 2 different mechanisms and targets.