Abstract 3195: The molecular mechanism of action and cellular targets of TTFields
Authors: Kalra Aarat P. , Xiao Jack , Hough Cameron , Kar Piyush , Rezania Vahid , Lewis John D. , Shankar Karthik , Tuszynski Jack A. 
Published: August 2018

Tumor Treating Fields (TTFields) are AC electric fields of intensity 1-2 V/cm in the frequency range 100-300 kHz, which have been shown to be an effective FDA-approved adjuvant therapy for Glioblastoma Multiforme. However, the mechanism of action for TTFields is not well understood. It is known that microtubules (MTs) and actin filaments re-orient themselves and behave abnormally when subjected to external electric fields indicating that they may be cellular targets of TTFields. The purpose of our study was to determine the molecular mechanism of action of TTFields. Previously, using impedance spectroscopy we observed the effect of unpolymerized tubulin and microtubules on ionic conductivity of buffer solution, and found that unlike tubulin, microtubules increased electrical conductance, which peaked at TTField-like frequencies1. Microtubules have been modeled as conductive cables that attract and guide counterions to increase the solution's conductance. protonic transport through the lumen of the microtubule has also been modeled. To investigate the additional possibility of electronic transport along α, β- tubulin dimers we are performing spectroscopic characterization of MTs. Using Dynamic Light Scattering (DLS) we have characterized the thickness of the solvation layer around the tubulin dimer, which elucidates the mechanism of ionic conduction. We have found that the thickness of the solvation layer increases as the concentration of a highly polar molecule such as DMSO is increased. We have found that increasing the solution temperature leads to a reduction of the solvation layer's thickness and have also characterized response to changes in pH of solution. We have polymerized various morphologies of tubulin assemblies, e.g. planar zinc sheets and (300-500 nm diameter) macrotubes to gain insight into associated conductivity processes. We have imaged these interesting morphologies using Transmission Electron Microscopy (TEM) and epifluorescence microscopy. Impedance spectroscopy of microtubules and actin filaments decorated with ligands such as microtubule associated proteins and drugs and anesthetics is under way. Numerical estimates of the magnitudes of the currents, energy and power generated in a cancer cell using TTFields have been computed. This research provides physical insights into the subcellular mechanisms involved in TTField therapy and can assist in its' optimization.

1.Santelices, Iara B., et al. "Response to Alternating Electric Fields of Tubulin Dimers and Microtubule Ensembles in Electrolytic Solutions." Scientific Reports 7.1 (2017): 9594.

Citation Format: Aarat P. Kalra, Jack Xiao, Cameron Hough, Piyush Kar, Vahid Rezania, John D. Lewis, Karthik Shankar, Jack A. Tuszynski. The molecular mechanism of action and cellular targets of TTFields [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3195.