Ion Channels as Therapeutic Targets 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.

An Alternative Pipeline for Glioblastoma Therapeutics: A Systematic Review of Drug Repurposing in Glioblastoma

“…By a similar mechanism, it was found that the combination of riluzole and sirolimus increased apoptosis in vitro and decreased growth in heterotopic murine GBM [ 71 ]. In addition to the above, riluzole is a thought to be a sodium channel blocker that inhibits glutamate release [ 72 ]. By this mechanism, riluzole was also shown to inhibit glucose transport 3 (GLUT3) in GSCs, resulting in inhibition of HIF1α and p-AKT signaling.…”

“…By this mechanism, riluzole was also shown to inhibit glucose transport 3 (GLUT3) in GSCs, resulting in inhibition of HIF1α and p-AKT signaling. Finally, riluzole was shown to downregulate DNA (cytosine-5-)-methyltransferase (DNMT1), a factor responsible for hypermethylation of tumor suppressors [ 72 ]. While riluzole has not been examined in patients, clinical studies with mTOR inhibitors are discussed in detail later.…”

Cell Systems Bioelectricity: How Different Intercellular Gap Junctions Could Regionalize a Multicellular Aggregate

“…In this scenario, Equations (1)–(4) constitute a minimum model based on conductances ultimately related to specific proteins. In principle, the transcription, translation, and post-translational gating of these ion channel and junction proteins are amenable to external modulation and future therapeutic strategies [ 3 , 12 , 13 , 15 , 45 , 56 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. Consequently, the bioelectrical patterns and their encoded information could be externally regulated by acting on multicellular mean field phenomena such as electrical potential, potassium, and calcium waves [ 3 , 4 , 5 , 9 , 72 , 73 ] as a complementary procedure to addressing individual cell characteristics.…”

Electrotherapies for Glioblastoma

“…In particularly, epithelial Na + channels which fall into amiloride‐sensitive Na + channels are associated with proliferation and invasion in many cancers. [ 53 ] Glioma ion channels [ 35 ] and inhibitors [ 39 ] used as a treatment modality have been reviewed. Combination of channel inhibitors with electrotherapy could lead to greater understanding of the cellular mechanism due to induced electric fields.…”