A Theoretical Study on the Biophysical Mechanisms by Which Tumor Treating Fields Affect Tumor Cells During Mitosis

Li, Xing; Yang, Fan; Rubinsky, Boris

doi:10.1109/tbme.2020.2965883

Cited by 41 publications

(58 citation statements)

References 35 publications

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“…Various studies have shown the effectiveness of using irreversible electroporation to induce tumor ablation and suggest that its ability to target malignant cells is due to plasma membrane differences between cancer and non-cancer cells [ 67 , 68 ]. The V m of both non-cancer and cancer cells depolarizes during proliferation, to about −15 mV, but post-mitotic non-cancer cells return to a typical resting V m of −70 mV whereas post-mitotic cancer cells achieve a resting V m of −25 mV [ 51 , 69 ]. The depolarized resting V m in cancer cells relative to that in non-cancer cells is thought to be caused by altered lipid and sterol membrane composition, which results in an influx of sodium ions into the cell and a collection of negative charges on the cell coat [ 70 ].…”

Section: Results: Explanatory Modelsmentioning

confidence: 99%

“…The consequence of this difference is that the resting V m needed to reach both the first and second thresholds is lower in cancer cells than in non-cancer cells. The relatively depolarized resting V m in cancer cells [ 28 , 29 , 30 , 31 , 73 , 74 , 75 ] could explain why, compared to non-cancer cells, cancer cells are more vulnerable to both electroporation and TTFields [ 67 , 69 ] (see Table S4 ). Table 4 compares the parameters between TTFields and electroporation (DC and AC).…”

Section: Results: Explanatory Modelsmentioning

confidence: 99%

“…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 ]. TTFields have been shown to affect other cellular structures.…”

Section: Discussionmentioning

confidence: 99%

“…Augmentation of field strength in adjacent membrane regions of densely packed cells (i.e., the tissue level) may lead to values that would be concordant with either the bioelectrorheological or electroporation models. Indeed, research by some of us (co-authors TM and ZB, personal communication) shows that finite element modeling predicts that when cells are in close proximity to each other, electric field lines are concentrated between the contact points in a frequency-dependent manner [ 51 , 69 ]. The unexpectedly high field strengths achieved in these regions may remove the obstacle of electric field strength being insufficient for bioelectrorheological and electroporative processes to be able to explain the empirical observation of membrane fenestration due to TTFields [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

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Permeabilizing Cell Membranes with Electric Fields

Aguilar

Chang

et al. 2021

Cancers

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The biological impact of exogenous, alternating electric fields (AEFs) and direct-current electric fields has a long history of study, ranging from effects on embryonic development to influences on wound healing. In this article, we focus on the application of electric fields for the treatment of cancers. In particular, we outline the clinical impact of tumor treating fields (TTFields), a form of AEFs, on the treatment of cancers such as glioblastoma and mesothelioma. We provide an overview of the standard mechanism of action of TTFields, namely, the capability for AEFs (e.g., TTFields) to disrupt the formation and segregation of the mitotic spindle in actively dividing cells. Though this standard mechanism explains a large part of TTFields’ action, it is by no means complete. The standard theory does not account for exogenously applied AEFs’ influence directly upon DNA nor upon their capacity to alter the functionality and permeability of cancer cell membranes. This review summarizes the current literature to provide a more comprehensive understanding of AEFs’ actions on cell membranes. It gives an overview of three mechanistic models that may explain the more recent observations into AEFs’ effects: the voltage-gated ion channel, bioelectrorheological, and electroporation models. Inconsistencies were noted in both effective frequency range and field strength between TTFields versus all three proposed models. We addressed these discrepancies through theoretical investigations into the inhomogeneities of electric fields on cellular membranes as a function of disease state, external microenvironment, and tissue or cellular organization. Lastly, future experimental strategies to validate these findings are outlined. Clinical benefits are inevitably forthcoming.

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Section: Results: Explanatory Modelsmentioning

confidence: 99%

Section: Results: Explanatory Modelsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Permeabilizing Cell Membranes with Electric Fields

Aguilar

Chang

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…Altering the cell membrane potential of a tumor cell in prophase and increasing Ca 2+ flow into the cell could decrease microtubule polymerization. The disruption of ionic homeostasis thus offers a unique explanation regarding the ability of TTFields to exhibit an anti-microtubule effect during the early stages of mitosis (23).…”

Section: Ttfields and Mechanisms For Anti-mitotic Effectsmentioning

confidence: 99%

Tumor Treating Fields: At the Crossroads Between Physics and Biology for Cancer Treatment

et al. 2020

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Despite extraordinary advances that have been achieved in the last few decades, cancer continues to represent a leading cause of mortality worldwide. Lethal cancer types ultimately become refractory to standard of care approaches; thus, novel effective treatment options are desperately needed. Tumor Treating Fields (TTFields) are an innovative non-invasive regional anti-mitotic treatment modality with minimal systemic toxicity. TTFields are low intensity (1-3 V/cm), intermediate frequency (100-300 kHz) alternating electric fields delivered to cancer cells. In patients, TTFields are applied using FDA-approved transducer arrays, orthogonally positioned on the area surrounding the tumor region, with side effects mostly limited to the skin. The precise molecular mechanism of the anti-tumor effects of TTFields is not well-understood, but preclinical research on TTFields suggests it may act during two phases of mitosis: at metaphase, by disrupting the formation of the mitotic spindle, and at cytokinesis, by dielectrophoretic dislocation of intracellular organelles leading to cell death. This review describes the mechanism of action of TTFields and provides an overview of the most important in vitro studies that investigate the disruptive effects of TTFields in different cancer cells, focusing mainly on anti-mitotic roles. Lastly, we summarize completed and ongoing TTFields clinical trials on a variety of solid tumors.

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Steering Piezocatalytic Therapy for Optimized Tumoricidal Effect

Zheng,

Lin,

Tian

et al. 2024

Adv Funct Materials

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Piezocatalysts, because of their mechano‐electrical conversion properties, are exploited for various medical applications, such as sterilization, tissue engineering, biosensing, and disease theranostics. In particular, based on the unique advantage of the piezoelectric effect, piezocatalytic therapy (PCT) has been developed as a novel and promising candidate for tumor therapy. To optimize the utilization of piezocatalysts in tumor therapy, a comprehensive understanding of the antitumor mechanism associated with these materials is imperative. Here, the piezocatalytic action principle is elucidated by investigating piezocatalysts, reactants, energy inputs, and products. Subsequently, the antitumor mechanisms of PCT have been extensively discussed and are recapitulative as follows: restraining cell proliferation, inducing cell programmed death, hindering tumor metastasis, inhibiting tumor angiogenesis, and enhancing antitumor immunity. Additionally, the optimized therapeutic outcomes of PCT‐centric synergistic cancer therapy are systematically described. Finally, the main challenges and future research directions of piezocatalysis applied in cancer therapy are envisioned. It is believed that PCT will serve as a new‐generation ingenious tool for cancer treatment.

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A Theoretical Study on the Biophysical Mechanisms by Which Tumor Treating Fields Affect Tumor Cells During Mitosis

Cited by 41 publications

References 35 publications

Permeabilizing Cell Membranes with Electric Fields

Permeabilizing Cell Membranes with Electric Fields

Tumor Treating Fields: At the Crossroads Between Physics and Biology for Cancer Treatment

Steering Piezocatalytic Therapy for Optimized Tumoricidal Effect

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