Abstract
The lack of treatment options for high-grade brain tumors has led to searches for alternative therapeutic modalities. Electrical field therapy is one such area. The Optune™ system is an FDA-approved novel device that delivers continuous alternating electric fields (tumor treating fields—TTFields) to the patient for the treatment of primary and recurrent Glioblastoma multiforme (GBM). Various mechanisms have been proposed to explain the effects of TTFields and other electrical therapies. Here, we present the first study of genome-wide expression of electrotherapy (delivered via TTFields or Deep Brain Stimulation (DBS)) on brain tumor cell lines. The effects of electric fields were assessed through gene expression arrays and combinational effects with chemotherapies. We observed that both DBS and TTFields significantly affected brain tumor cell line viability, with DBS promoting G0-phase accumulation and TTFields promoting G2-phase accumulation. Both treatments may be used to augment the efficacy of chemotherapy in vitro. Genome-wide expression assessment demonstrated significant overlap between the different electrical treatments, suggesting novel interactions with mitochondrial functioning and promoting endoplasmic reticulum stress. We demonstrate the in vitro efficacy of electric fields against adult and pediatric high-grade brain tumors and elucidate potential mechanisms of action for future study.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive adult primary brain tumor [1]
We have shown that both electrical treatments (TTFields and Deep Brain Stimulating (DBS)) exhibit efficacy against adult and pediatric brain tumor cell lines in vitro, and this efficacy increased with optimization of frequency and other parameters
DBS electric field efficacy was increased through increasing the intensity of the field and through manipulation of frequency between 60 Hz and 190 Hz
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive adult primary brain tumor [1]. In contrast to TTFields, DBS are internalized wires implanted surgically into the brain parenchyma They have shown considerable success in treating movement disorders such as Parkinson’s disease, through delivery of electrical fields to designated anatomical targets such as the subthalamic nucleus or globus pallidus. We present our investigations into the effects of TTFields on pediatric brain tumor cell lines as well as comparative studies into the use of repurposed DBS electrodes as delivery devices for low frequency electric fields. We demonstrate how electric field treatments of varying intensities and frequencies delivered by either TTFields or DBS electrodes significantly affect primary and commercial brain tumor cell line viability and cell cycling, while not affecting the viability of non-dividing astrocyte cells. We present genome-wide expression analysis of electric field-treated GBM cells, examining the genetic effects of both TTFields and DBS treatments on tumor cells, giving further suggestions to possible mechanisms of action
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