An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields

Abstract

Long-standing research on electric and electromagnetic field interactions with biological cells and their subcellular structures has mainly focused on the low- and high-frequency regimes. Biological effects at intermediate frequencies between 100 and 300 kHz have been recently discovered and applied to cancer cells as a therapeutic modality called Tumor Treating Fields (TTFields). TTFields are clinically applied to disrupt cell division, primarily for the treatment of glioblastoma multiforme (GBM). In this review, we provide an assessment of possible physical interactions between 100 kHz range alternating electric fields and biological cells in general and their nano-scale subcellular structures in particular. This is intended to mechanistically elucidate the observed strong disruptive effects in cancer cells. Computational models of isolated cells subject to TTFields predict that for intermediate frequencies the intracellular electric field strength significantly increases and that peak dielectrophoretic forces develop in dividing cells. These findings are in agreement with in vitro observations of TTFields’ disruptive effects on cellular function. We conclude that the most likely candidates to provide a quantitative explanation of these effects are ionic condensation waves around microtubules as well as dielectrophoretic effects on the dipole moments of microtubules. A less likely possibility is the involvement of actin filaments or ion channels.

Cell Death and Induced p53 Expression in Oral Cancer, HeLa, and Bone Marrow Mesenchyme Cells under the Exposure to Noncontact Electric Fields

“…During this process, plasma membrane breakage took place and many small abnormal membrane blebs formed, corresponding to postmitotic apoptotic cell death [43,44]. At the subcellular level, electric fields may interfere with the normal polymerization-depolymerization process of microtubules during mitosis [12,45,46,47]. The inhibition of the proliferation of oral cancer and HeLa cells may suggest that treatment with low-intensity and intermediate-frequency noncontact electric fields by ECCT is quite effective and should be performed in an in vivo study on an animal model.…”

A Review on Tumor-Treating Fields (TTFields): Clinical Implications Inferred From Computational Modeling

“…These two theories were recently evaluated in a theoretical analysis by Tuszyński et al [20]. According to this analysis, the DEP forces that develop during telophase are indeed strong enough to interfere with mitosis.…”

“…According to images of the division process [43], as the cell proceeds into telophase elliptical cell shapes with equal size become more appropriate to characterize the process in which the daughter cells form. To reflect these geometries, studies simulating TTFields application to single cells [20], [44]- [46] assumed a spherical cell with a default radius of 10 μm during metaphase. During telophase and cytokinesis, elliptical sister cells with a default major radius of 10 μm and a minor radius of 7 μm were considered.…”

“…Since a large range of properties are expected within the population of glial cells [46], different ranges of these parameters were tested to investigate how the dielectric properties of cells influence their response to TTFields (see Section II-A-2). The computational studies [20], [44]- [46] were carried out using the Electric Currents Interface of the ac/dc module of Comsol Multiphysics (www.comsol.com). The thin membrane was numerically represented by the contact impedance BC available in Comsol.…”

“…It has been speculated that when dividing cells are exposed to TTFields, the tubulin dimers align with the field rather than with the growing MT axis. However, Tuszyński et al [20] calculated that the interaction energy of a tubulin dimer with an EF of 1 V/cm is too small to affect the dynamics of the dimer. They also proposed that a 1 V/cm EF would be insufficient to exert a major influence on MTs and the cytoskeleton due to Debye screening.…”