An Evidence-Based Review of Alternating Electric Fields Therapy for Malignant Gliomas

Tumor treating fields (TTFields) represent a novel treatment modality for cancer that utilizes alternating electric fields at an intermediate frequency of 200 kHz. At this specific frequency, TTFields have been shown to penetrate into the head from the surface of the scalp. Computational modeling also showed that the fields are distributed inhomogeneously within the supratentorial regions of the brain, and they tend to become intensified near the ventricles [ 1 •]. At the cellular level, the electromagnetic energy perturbs proteins that have large dipole moments. Cells treated with TTFields exhibited a variety of abnormalities indicative of mitotic catastrophe and aberrant mitotic exit, including cells in polyploidy prophase, rosettes, multi-spindled metaphase, single-spindled metaphase, and asymmetric anaphase [ 2 ]. Indeed, cells exhibit violent membrane blebbing as they enter anaphase and attempt to divide. This results in aberrant mitotic exit and subsequent cell death [ 3 ••]. Some of the proteins that are critical for the proper progression through mitosis have sufficiently high dipole moments to suggest that they may be targets of TTFields, including the mitotic septin complex and the α/β-tubulin monomeric subunit of tubulin. Septins constitute a family of GTP-binding proteins and septin 2, 6, and 7 oligomerize into a heterotrimer with an extremely large dipole moment of 2711 Debyes [ 4 ]. Importantly, this septin complex is required for functions that are necessary for the later stages of cell division. Septin 2, 6, and 7 heterotrimers rapidly polymerize and structurally organize within the cytokinetic furrow as cells exit metaphase. Once it is recruited, it then organizes contractile elements within the cytokinetic furrow above the equatorial cleavage plane by binding to F-actin filaments and spatially regulates myosin activation. RNAi-directed depletion of septin subunits of the heterotrimer results in mitotic catastrophe similar to that seen when cells attempt to divide in the presence of TTFields [ 5 ]. We have shown that TTFields disrupt the ability of septins to re-localize to the cytokinetic furrow and reduce the accumulation of F-actin [ 3 ••]. Therefore, TTFields affect tumor cells by interfering with their ability to complete mitosis by exerting electromagnetic induction forces that interfere with the function of proteins with high dipole moments [ 2 , 3 ••].