Objective: A theoretical study on the mechanisms through which Tumor Treating Fields (TTFields) affect dividing tumor cells. Methods: Numerical analysis was used to revisit two previously proposed mechanisms and introduce a third. We examine the previous hypotheses that: a) TTFields generate a moment that affects microtubule assembly during early mitosis, and b) dielectrophoretic (DEP) forces cause neutral particles to move toward the cleavage furrow during the telophase stage. We further introduce a new hypothesis that TTFields modify cell membrane potential in dividing tumor cells. Results: a) The Brownian energy is several orders of magnitude larger than the moment induced by TTFields on tubulin dimers. b) Adding Stokes drag forces to DEP forces shows that the motion of the particles in the cytoplasm is very slow, approximately 0.003 μm/s, and therefore, unless the duration of the telophase is long enough there will be no substantial effect from the DEP forces. c) The Schwan equation shows that electric fields at the frequencies of clinical TTFields can cause a 10% - 17% change in tumor cell membrane potential. Conclusion: Our studies find limited support for the previously suggested hypotheses and suggest that the TTFields effect on cell membrane potential by affecting ion channels could be a mechanism of tumor cell death. Significance: Previously suggested mechanisms of tumor cell death from TTFields are found lacking. The effect of TTFields on the tumor cell membrane potential warrants further research.

Background: Tumor Treating Fields (TTFields) is a non-invasive modality for cancer treatment that utilizes a specific sinusoidal electric field ranging from 100 kHz to 300 kHz, with an intensity of 1 V/cm to 3 V/cm. Its purpose is to inhibit cancer cell proliferation and induce cell death. Despite promising outcomes from clinical trials, TTFields have received FDA approval for the treatment of glioblastoma multiforme (GBM) and malignant pleural mesothelioma (MPM). Nevertheless, global acceptance of TTFields remains limited. To enhance its clinical application in other types of cancer and gain a better understanding of its mechanisms of action, this review aims to summarize the current research status by examining existing literature on TTFields’ clinical trials and mechanism studies. Conclusions: Through this comprehensive review, we seek to stimulate novel ideas and provide physicians, patients, and researchers with a better comprehension of the development of TTFields and its potential applications in cancer treatment.

Objective: Clinical studies show that low intensity (single V/cm), intermediate-frequency (100 kHz-300 kHz) electric fields inhibit the growth of cancer cells, while the mechanism is not yet understood. We examine the hypothesis that electric fields modify the cell membrane potential of dividing cancer cells in a way that correlates with cells growth inhibition. Methods: A Schwan based mathematical model calculates the changes in HeLa cells membrane potential due to single V/cm electric fields and frequencies from 0.1 to 1 MHz. An experimental study examines the effect of these electric fields on the inhibition of HeLa cells growth in an incubator. Results: The theoretical calculation shows that the effects of these electric fields on cell membrane potential decrease with an increase in frequency. The HeLa cells experiments verified the inhibitory effect of these fields on cell growth. The inhibitory effect is decreasing with an increase in frequency, in a way that is similar to the frequency dependent effect of these fields on the cell membrane potential. Conclusions: The superposition of the theoretical results and the experimental results suggest a correlation between the effect of these fields on the cell membrane potential and inhibition of cancer cell growth. It should be emphasized that correlations do not prove causality, however, they suggest an area for future research. Significance: These findings have value for the understanding of the mechanisms of cancer cells growth inhibition with electric fields and suggest an interesting area of research on the interaction between electromagnetic fields and cancer cells.

Tumor treating fields (TTFields) are a type of sinusoidal alternating current electric field that has proven effective in inhibiting the reproduction of dividing tumor cells. Despite their recognized impact, the precise biophysical mechanisms underlying the unique effects of TTFields remain unknown. Many of the previous studies predominantly attribute the inhibitory effects of TTFields to mitotic disruption, with intracellular microtubules identified as crucial targets. However, this conceptual framework lacks substantiation at the mesoscopic level. This study addresses the existing gap by constructing force models for tubulin and other key subcellular structures involved in microtubule electrophysiological activities under TTFields exposure. The primary objective is to explore whether the electric force or torque exerted by TTFields significantly influences the normal structure and activities of microtubules. Initially, we examine the potential effect on the dynamic stability of microtubule structures by calculating the electric field torque on the tubulin dimer orientation. Furthermore, given the importance of electrostatics in microtubule-associated activities, such as chromosome segregation and substance transport of kinesin during mitosis, we investigate the interaction between TTFields and these electrostatic processes. Our data show that the electrodynamic effects of TTFields are most likely too weak to disrupt normal microtubule electrophysiological activities significantly. Consequently, we posit that the observed cytoskeleton destruction in mitosis is more likely attributable to non-mechanical mechanisms.