An overview of potential novel mechanisms of action underlying Tumor Treating Fields-induced cancer cell death and their clinical implications

Abstract

Traditional cancer therapy choices for clinicians are surgery, chemotherapy, radiation and immune therapy which are used either standalone therapies or in various combinations. Other physical modalities beyond ionizing radiation include photodynamic therapy and heating and the more recent approach referred to as Tumor Treating Fields (TTFields). TTFields are intermediate frequency, low-intensity, alternating electric fields that are applied to tumor regions and cells using noninvasive arrays. TTFields have revolutionized the treatment of newly diagnosed and recurrent glioblastoma (GBM) and unresectable and locally advanced malignant pleural mesothelioma (MPM). TTFields are thought to kill tumor cells predominantly by disrupting mitosis; however it has been shown that TTFields increase efficacy of different classes of drugs, which directly target mitosis, replication stress and DNA damage pathways. Hence, a detailed understanding of TTFields' mechanisms of action is needed to use this therapy effectively in the clinic. Recent findings implicate TTFields' role in different important pathways such as DNA damage response and replication stress, ER stress, membrane permeability, autophagy, and immune response. This review focuses on potentially novel mechanisms of TTFields anti-tumor action and their implications in completed and ongoing clinical trials and pre-clinical studies. Moreover, the review discusses advantages and strategies using chemotherapy agents and radiation therapy in combination with TTFields for future clinical use.

Permeabilizing Cell Membranes with Electric Fields

“…Mitotic disruption by exogenously imposed electric fields have been reported [ 8 ]; however, mitotic spindles are not the only biological structures that possess intrinsic dipole moments. To illustrate, DNA itself possesses intrinsic dipole moments and recent investigations have revealed that TTFields may have effects on DNA damage response and replication stress, ER stress, membrane permeability, autophagy, and immune response [ 5 ]. In addition, recent modeling studies in the context of dipole alignment suggest that the magnitude of the electric field caused by TTFields may not be sufficient to overcome Brownian motion inherent within the cytoplasm of single cancer cells [ 51 , 69 ].…”

“…Advances in techniques to measure voltage and current gradients in biological material coupled with imaging technology to assess morphological changes in organisms have revealed that exposure to electro-magnetic occurrences can trigger a range of morphometric processes from embryological development to wound healing [2][3][4]. Frequencies for biologically relevant exposure to electromotive forces (EMFs) can range from being very low (0-300 Hz) to intermediate values (30 Hz to 400 kHz) to high and very high frequencies (1 MHz to 10 GHz, see Figure 1 [2,5]). Different EMF ranges will initiate different biological effects (Figure 1).…”

“…In addition to destabilizing microtubules, AEFs may affect the formation of proteins involved with the mitotic spindle complex, e.g., septins [ 24 , 25 ]. Investigations have been made to examine the role of AEFs in disrupting DNA replication, inducing autophagy, and impacting immune cell viability and function [ 5 ]. Recently we have demonstrated that TTFields exposure, in conjunction with a novel anti-cancer compound Withaferin A, synergistically inhibited the growth of human glioblastoma cells [ 26 ].…”

An overview on tumor treating fields (TTFields) technology as a new potential subsidiary biophysical treatment for COVID-19

“…Additionally, as far as mentioned above, TTFields enhances autophagy, and increasing autophagy in SARS-COV-2 virally infected cells can lead to apoptosis in them[ 96 , 106 , 107 , 117 ]. Hence, it can be supposed that TTFields can induce apoptosis in SARS-COV-2 virally infected cells subsequently disrupt the viral replication cycle.…”

Skull Modulated Strategy to Intensify Tumor Treating Fields on Brain Tumor: a Finite Element Study

“…But the high recurrence rate usually leads to more restricted treatments and a worse prognosis 2 . Although many pieces of research have presented promising e cacy in their preliminary phases, the majority of phase III clinical trials have failed, including cytotoxic drugs 3,4 , targeted therapies 5-7 , immunotherapies 8,9 , and oncolytic viruses 10 .…”