Subtype-specific block of glioblastoma motility through dual inhibition of water and ion flux.

Abstract

The aggressive invasion of glioma cells into healthy brain parenchyma makes glioblastoma multiforme (GBM) difficult to overcome with current treatment regimens, which are cytotoxic and not localised to the primary tumour site. Further limitations are imposed by extensive cellular heterogeneity within glioblastoma tumours, which can leave treatment-resistant cells intact and poised to initiate relapse. Targeting unique subsets of proteins implicated in cellular motility pathways, namely water and ion channels, could present a novel means of controlling glioblastoma invasion. Pharmacological inhibition of selected ion channels and aquaporin water channels that are upregulated in GBM decreased invasiveness of U87-MG and U251-MG glioblastoma cells in vitro at non-cytotoxic doses. Notably, combining ion channel blockers with aquaporin-1 inhibitor AqB013 evoked additive inhibition of invasion. These additive effects differed between cell lines, consistent with the differences in ion channel and water channel expression profiles in U87-MG and U251-MG.Impeding glioblastoma tumour invasion by concurrently targeting aquaporins and ion channels with functions in cellular motility pathways could constitute a powerful adjunct therapy when applied in parallel with existing therapies. Classes of channels that would be optimal targets for combined therapies could be tailored to GBM cancer cell subtypes. Administering specific combinations of aquaporin and ion channel antagonists at low doses could provide effective means of overcoming signalling pathway redundancy in GBM cells, exploiting the differences in channel expression patterns unique to each subtype while minimising toxicity in surrounding tissue. In response to ongoing calls for new therapeutic interventions for glioblastoma, this work proposes that simultaneous inhibition of water and ion movement in motile glioma cells can halt GBM cell spread and could augment the effectiveness of current standard practices used for eradicating primary tumours, constituting a promising addition to the targeted cancer therapy repertoire.