A Bioelectric Therapy for Glioblastoma: Stimulating Purinergic Signaling via Pulsed Electric Fields

Glioblastoma is a highly aggressive brain cancer with limited treatment options due to the blood-brain barrier and the development of acquired chemoresistance. Bioelectric therapies, including pulsed electric field (PEF) treatment, have shown promise in cancer therapy by affecting tumor cells and their microenvironment. This study explores the potential of thin-film electronics for PEF treatments targeting glioblastoma, with a focus on ATP-mediated calcium signaling. PEFs applied through bare gold and PEDOT:PSS-coated electrodes induce a transient increase in intracellular calcium, mediated by mechanisms depending on cell location: electroporation near the electrodes and ATP-mediated signaling for cells located further away. Luminescence assays reveal that PEFs trigger ATP release into the extracellular space, with higher levels observed with PEDOT:PSS-coated electrodes, despite reduced electroporation effects. The involvement of ATP-permeable channels and purinergic receptors in calcium signaling is confirmed by selective channel blockers. These findings suggest that PEFs, even in the absence of cell electroporation, stimulate ATP release, activating purinergic receptors and inducing calcium influx in cells not only near the electrodes. Beyond triggered ATP depletion, ATP may act as a damage-associated molecular pattern, potentially contributing to immune modulation at the tumor site. This highlights the potential of thin-film electrodes for non-invasive electrotherapy in glioblastoma treatment.