Quantifying the Effect of Electric Fields in the Frequency Range of 100-500 khz on Mitotic Spindle Structures

Abstract

It is well established that electric fields can influence cells: Low frequency electric fields (f 1 MHz) cause tissue heating. More recently, it was shown that exposing dividing cells to low intensity (∼1 V/cm) electric fields in the frequency range of 100 - 500 kHz leads to disruption of the mitotic process, and ultimately cell death. This discovery motivated the development of Tumor Treating Fields (TTFields) therapy: a non-invasive treatment that utilizes electric fields in the intermediate frequency range to treat solid tumors. TTFields have been approved by the US Food and Drug Administration for the treatment of recurrent glioblastoma multiforme since 2011.It is thought that TTFields exert their effect on cells by inhibiting tubulin polymerization through interactions of the electric fields with the highly polarized tubulin dimers. However, only few studies have been performed that quantify the intracellular intensity of electric fields, in the frequency range of 100-500 kHz, and how these fields disrupt tubulin polymerization. Here we present the results of computational simulations and in-vitro studies that address these issues. The simulations show that the frequency range of 100-500 kHz marks a transition region in which the magnitude of the electric field inside cells increases significantly, and that the threshold at which this increase occurs depends on the dielectric properties of the cell's membrane and cytoplasm. The experiments show that exposure of cell cultures to TTFields leads to a 10-20% increase in the amount of unpolymerized tubulin dimers within the cells, suggesting that TTFields influence tubulin polymerization dynamics. These studies provide new insight into the biophysical mechanisms that underlie TTFields therapy.