Ion Channels as Therapeutic Targets in High Grade Gliomas

SIMPLE SUMMARY: Glioblastoma multiforme is an aggressive grade IV lethal brain tumour with a median survival of 14 months. Despite surgery to remove the tumour, and subsequent concurrent chemotherapy and radiotherapy, there is little in terms of effective treatment options. Because of this, exploring new treatment avenues is vital. Brain tumours are intrinsically electrically active; expressing unique patterns of ion channels, and this is a characteristic we can exploit. Ion channels are specialised proteins in the cell’s membrane that allow for the passage of positive and negatively charged ions in and out of the cell, controlling membrane potential. Membrane potential is a crucial biophysical signal in normal and cancerous cells. Research has identified that specific classes of ion channels not only move the cell through its cell cycle, thus encouraging growth and proliferation, but may also be essential in the development of brain tumours. Inhibition of sodium, potassium, calcium, and chloride channels has been shown to reduce the capacity of glioblastoma cells to grow and invade. Therefore, we propose that targeting ion channels and repurposing commercially available ion channel inhibitors may hold the key to new therapeutic avenues in high grade gliomas. ABSTRACT: Glioblastoma multiforme (GBM) is a lethal brain cancer with an average survival of 14–15 months even with exhaustive treatment. High grade gliomas (HGG) represent the leading cause of CNS cancer-related death in children and adults due to the aggressive nature of the tumour and limited treatment options. The scarcity of treatment available for GBM has opened the field to new modalities such as electrotherapy. Previous studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence indicates that not only are ion channels key in regulating electrical signaling and membrane potential of excitable cells, they perform a crucial role in the development and neoplastic progression of brain tumours. Unlike other tissue types, neural tissue is intrinsically electrically active and reliant on ion channels and their function. Ion channels are essential in cell cycle control, invasion and migration of cancer cells and therefore present as valuable therapeutic targets. This review aims to discuss the role that ion channels hold in gliomagenesis and whether we can target and exploit these channels to provide new therapeutic targets and whether ion channels hold the mechanistic key to the newfound success of electrotherapies.