Permeabilizing Cell Membranes with Electric Fields
Open accessAbstract
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.
AI snapshot
Written from the paper’s full text.
TL;DR
This review summarizes proposed mechanisms by which alternating electric fields (AEFs), including tumor treating fields (TTFields), permeabilize cancer cell membranes. It concludes that no single model fully explains TTFields’ membrane effects and that a combination of bioelectrorheological and electroporation mechanisms, potentially amplified by tissue-level field inhomogeneities, is most likely.
Key findings
- In newly diagnosed glioblastoma, 200 kHz TTFields plus adjuvant temozolomide prolonged median overall survival by 4.9 months and median progression-free survival by 2.7 months versus adjuvant temozolomide alone; the 5-year overall survival rate increased from 5% to 13%.
- In malignant pleural mesothelioma, 150 kHz TTFields with pemetrexed and platinum-based chemotherapy produced median overall survival of 18.2 months and median progression-free survival of 7.6 months, compared with historical controls of 12.1 months and 5.7 months.
- TTFields exposure induced membrane fenestrae in cancer cells with cross-sectional areas of 240.6 ± 91.7 nm², corresponding to diameters of 17.5 ± 10.8 nm.
- Three mechanistic models are reviewed—voltage-gated ion channel activation, bioelectrorheological effects, and electroporation—but inconsistencies were noted in effective frequency range and field strength between TTFields and all three models; the authors conclude the explanation most likely combines bioelectrorheological and electroporation models.
Methods
- Narrative review of current literature on AEFs/TTFields and cell membranes, including clinical trial data in glioblastoma and mesothelioma and preclinical/mechanistic studies.
- The paper compares three explanatory models against TTFields parameters and discusses theoretical investigations into electric field inhomogeneities on cellular membranes as a function of disease state, external microenvironment, and tissue or cellular organization.
- Main analysis is conceptual synthesis and model comparison, with proposed future experimental strategies; no new primary experimental data are reported.
Limitations
- The paper states that inconsistencies exist in both effective frequency range and field strength between TTFields and all three proposed models, and that most computational modeling studies are based on single cells in isolation.
- The paper states that further dedicated studies are needed to resolve gaps and provide a more complete understanding of TTFields’ membrane-permeabilizing effects.
- Evident from the text: as a review, it relies on cited studies and personal correspondence/unpublished modeling, and some cited evidence is correlative rather than causal (e.g., Neuhaus et al. showed correlation of AEF effects on Cav1.2 channels with TTFields’ effects, but not causation).
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
0 of 144 cited sources checked · 0 supported · 0 flagged
- Findingcitation
TTFields and Withaferin A have synergistic activity.
“Such a phenomenon may explain our recent findings of synergistic activity between TTFields and the potential chemotherapeutic agent, Withaferin A [26].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Chang, 2017, Synergistic inhibition of glioma cell proliferation by Withaferin A and tumor treating fields, J. Neuro Oncol. source
Not checked in the free run.
- Findingcitation
TTFields induce fenestrae in the plasma membrane, as previously observed with scanning electron microscopy.
“The ability to enhance the efficacy of chemotherapeutics may be explained by the induction of fenestrae in the plasma membrane by TTFields, which we previously observed with scanning electron microscopy [27].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] Chang, 2018, Tumor treating fields increases membrane permeability in glioblastoma cells, Cell Death Discov. source
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- Findingnone given
In our investigations, inconsistencies were noted in both the effective frequency range and field strength between TTFields versus all three proposed models.
“In our investigations, inconsistencies were noted in both the effective frequency range and field strength between TTFields versus all three proposed models.”
Quote in the paperNot a substantial claim - Findingcitation
Finite element modeling predicts that when cells are in close proximity, electric field lines are concentrated between contact points in a frequency-dependent manner.
“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].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [51] Li, 2020, A Theoretical Analysis of the Effects of Tumor-Treating Electric Fields on Single Cells, Bioelectromagnetics source
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- cites [69] Li, 2020, A Theoretical Study on the Biophysical Mechanisms by Which Tumor Treating Fields Affect Tumor Cells During Mitosis, IEEE Trans. Biomed. Eng. source
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- Premisecitation
TTFields force microtubular filaments to align along electric field lines, interrupting the functionality of the mitotic spindle in actively dividing cells.
“By forcing microtubular filaments to align along electric field lines through the exogenous imposition of TTFields, the functionality of the mitotic spindle is interrupted in actively dividing cells [18] thereby disrupting replication [8,9,19]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Hottinger, 2016, Tumor treating fields: A novel treatment modality and its use in brain tumors, Neuro Oncol. source
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- Premisecitation
A randomized controlled open-label phase III clinical trial in malignant pleural mesothelioma patients reported a median overall survival of 16.1 months in its control arm of pemetrexed and cisplatin.
“Of note, a randomized controlled open-label phase III clinical trial in MPM patients published in 2016 demonstrated a median OS in its control arm (pemetrexed and cisplatin) of 16.1 months [15].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Zalcman, 2016, Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): A randomised, controlled, open-label, phase 3 trial, Lancet source
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- Interpretationnone given
Analytical models show that the low electric field intensity (1-3 V/cm) delivered by TTFields to single rounded cells cannot generate significant physical effects in the cytoplasm, such as dielectrophoretic force, electrostatic pressure, dipole orientation, or heat.
“In theoretical studies (by authors TM and ZB, personal correspondence), analytical models demonstrate that the low-electric field intensity (1–3 V/cm) delivered by TTFields to single rounded cells cannot generate significant physical effects (e.g., dielectrophoretic force, electrostatic pressure, dipole orientation, or heat) in the cytoplasm.”
Quote in the paperNot a substantial claim - Premisecitation
Cancer cells possess a relatively more depolarized resting membrane potential compared to non-cancer cells.
“Indeed, cancer cells are known to possess a relatively more depolarized resting membrane potential compared to non-cancer cells [28,29,30,31].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [28] Lobikin, 2012, Resting potential, oncogene-induced tumorigenesis, and metastasis: The bioelectric basis of cancerin vivo, Phys. Biol. source
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- cites [29] Marino, 1994, Association between Cell Membrane Potential and Breast Cancer, Tumor Biol. source
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- cites [30] Tokuoka, 1957, The membrane potential of the human cancer and related cells. I, Gan
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- cites [31] Yang, 2013, Membrane potential and cancer progression, Front. Physiol. source
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- Premisecitation
The overall survival benefit from adding 200 kHz TTFields was maintained across glioblastoma patient subgroups defined by MGMT promoter methylation status, extent of resection, region, age, Karnofsky performance score, and sex.
“The OS benefit due to the addition of 200 kHz TTFields therapy was maintained regardless of glioblastoma patient subgroup, i.e., MGMT promoter methylation status, extent of resection (biopsy, partial, gross total), region (U.S. vs. non-U.S.), age (<65 vs. ≥65 years), Karnofsky performance score (90–100 vs. ≤80), and sex [12].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Stupp, 2017, Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs. Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma, JAMA source
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- Premisecitation
In 2019, 150 kHz TTFields received FDA approval for first-line treatment of unresectable, locally advanced or metastatic malignant pleural mesothelioma when combined with pemetrexed and platinum-based chemotherapy.
“More recently, in 2019, 150 kHz TTFields received FDA approval under its humanitarian device exemption for the first-line treatment of unresectable, locally advanced or metastatic, malignant pleural mesothelioma (MPM) when combined with pemetrexed and platinum-based chemotherapy [13].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Ceresoli, 2019, Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): A multicentre, single-arm phase 2 trial, Lancet Oncol. source
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- Premisecitation
The 5-year overall survival rate increased from 5% to 13% in the glioblastoma patient arm receiving 200 kHz TTFields.
“Of note, the 5-year OS rate increased from 5% to 13% in the glioblastoma patient arm receiving 200 kHz TTFields [12].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Stupp, 2017, Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs. Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma, JAMA source
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- Premisecitation
TTFields induce fenestrae in cancer cellular membranes through increases in the size and number of observed membrane openings post-exposure, as shown by scanning electron microscopy.
“As shown by scanning electron microscopy (SEM), TTFields induce fenestrae in cancer cellular membranes through increases in the size and number of observed membrane openings post-exposure [27].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] Chang, 2018, Tumor treating fields increases membrane permeability in glioblastoma cells, Cell Death Discov. source
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- Premisecitation
TTFields exposure in conjunction with Withaferin A synergistically inhibited the growth of human glioblastoma cells.
“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].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Chang, 2017, Synergistic inhibition of glioma cell proliferation by Withaferin A and tumor treating fields, J. Neuro Oncol. source
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- Interpretationown data
AEFs, and TTFields in particular, share many characteristics with reversible electroporation.
“Third, AEFs, and TTFields in particular, share many characteristics with reversible electroporation (Figure 3C and Table S3).”
Quote in the paperSubstantial claim - Interpretationcitation
The frequency of TTFields (100-300 kHz) would seem to preclude effects such as initiation and propagation or blocking of action potentials in nerve cells, because such effects are not seen above ~30-50 kHz.
“Prima facie, while the amplitude of TTFields is sufficient to modulate ion channels in the cell membrane, the frequency of TTFields (100–300 kHz) would seem to preclude effects such as initiation and propagation or blocking of action potentials in nerve cells, because such effects are not seen above ~30–50 kHz [2].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Funk, 2009, Electromagnetic effects—From cell biology to medicine, Prog. Histochem. Cytochem. source
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- Interpretationcitation
If TTFields act on voltage-gated Cav2+ channels, the channel diameter of a few nanometers is too small to associate them with the pores created or enlarged by TTFields, which had cross-sectional areas of 240.6 ± 91.7 nm2 and diameters of 17.5 ± 10.8 nm.
“However, if we assume TTFields act on voltage-gated Cav2+ channels, the diameter of the channels is on the order of a few nanometers and therefore is too small to associate them with the pores shown by Chang et al. to be created or enlarged by TTFields, which had cross-sectional areas of 240.6 ± 91.7 nm2 [27], representing diameters of 17.5 ± 10.8 nm.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] Chang, 2018, Tumor treating fields increases membrane permeability in glioblastoma cells, Cell Death Discov. source
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- The authors state this as an assumption: TTFields act on voltage-gated Cav2+ channels.
- Premisecitation
Dividing cells are affected by TTFields during mitosis.
“Indeed, cellular and pre-clinical studies have demonstrated that dividing cells are affected by TTFields during mitosis [8,37].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [8] Giladi, 2016, Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells, Sci. Rep. source
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- cites [37] Wong, 2015, An Evidence-Based Review of Alternating Electric Fields Therapy for Malignant Gliomas, Curr. Treat. Options Oncol. source
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- Premisecitation
In Neuhaus et al., anti-clonogenicity was significant but low at 10% after 5-7 days.
“They noted that anti-clonogenicity was significant but low at 10% after 5–7 days [46].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [46] Neuhaus, E., Zirjacks, L., Ganser, K., Klumpp, L., Schüler, U., Zips, D., Eckert, F., and Huber, S.M. (2019). Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells. Cancers, 11. source
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- Interpretationnone given
Alternating electric fields of 1 kHz to 1 MHz can theoretically impose shear stress on membranes, leading to membrane distortions and potential changes in permeability.
“Second, alternating electric fields of 1 kHz to 1 MHz can theoretically impose shear stress on membranes, leading to membrane distortions and potential changes in permeability (the “bioelectrorheological model”, as shown in Figure 3B and Table S2).”
Quote in the paperNot a substantial claim - Premisenone given
Electroporation can increase the permeability of the cell membrane, permitting drugs that cannot normally gain access via the lipid membrane to enter the cells.
“Electroporation, or electropermeabilization, is of particular interest to this review because this process can increase the permeability of the cell membrane, which would permit drugs that cannot normally gain access via the lipid membrane to enter the cells.”
Quote in the paperSubstantial claim - Premisecitation
In N. crassa, the bioelectrorheological model predicted changes in cell volume and surface caused by AEFs of 3000 kHz.
“Further testing in N. crassa (mold cells) showed that the model was able to predict changes in cell volume and surface caused by AEFs of 3000 kHz [54].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [54] Fikus, 1989, Bioelectrorheological model of the cell. 2. Analysis of creep and its experimental verification, J. Theor. Biol. source
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- The authors state this as an assumption: In the bioelectrorheological framework, the cell model consists of cytoplasm, membrane, and external medium simplified as homogeneous, with cytoplasm and medium considered non-viscous fluids and the membrane considered an elastic and viscous element.
- Interpretationreasoning
The bioelectrorheological model provides a possible explanation for the causes of electroporation by demonstrating the combined effects of heat energy and extensile stress leading to reversible cell membrane destabilization, which can directly result in electroporation.
“Although the electric field strengths studied by Pawlowski and colleagues [40,53,54,55,56,57] were two orders of magnitude greater than that of TTFields, the bioelectrorheological model provides a possible explanation to the causes of electroporation by demonstrating the combined effects of heat energy and extensile stress leading to reversible cell membrane destabilization, which can directly”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [40] Fikus, 1993, Bioelectrorheological model of the cell. Analysis of the extensil deformation of cellular membrane in alternating electric field, Biophys. J. source
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- cites [53] Pawlowski, 1989, Bioelectrorheological model of the cell Analysis of stresses and deformations, J. Biol.
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- cites [54] Fikus, 1989, Bioelectrorheological model of the cell. 2. Analysis of creep and its experimental verification, J. Theor. Biol. source
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- cites [55] Szutowicz, 1993, Bioelectrorheological model of the cell. 5. Electrodestruction of cellular membrane in alternating electric field, Biophys. J. source
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- cites [56] Pawlowski, 1996, Bioelectrorheological model of the cell. VI. Experimental verification of the rheological model of cytoplasmic membrane, Biophys. J. source
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- cites [57] Poznanski, 1992, Bioelectrorheological model of the cell. Viscoelastic shear deformation of the membrane, Biophys. J. source
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- The authors state this as an assumption: In the bioelectrorheological framework, the cell model consists of cytoplasm, membrane, and external medium simplified as homogeneous, with cytoplasm and medium considered non-viscous fluids and the membrane considered an elastic and viscous element.
- Premisecitation
In Tib9 mouse myeloma plasma cells, the energy for electroporation was less than that needed for electro-destruction.
“In another study by Pawlowski and colleagues, the simplified model of a cell as a homogenous shell was used to demonstrate the electroporating effects of AEFs on Tib9 mouse myeloma plasma cells [55]. The energy for electroporation in these cells was less than that needed for electro-destruction.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [55] Szutowicz, 1993, Bioelectrorheological model of the cell. 5. Electrodestruction of cellular membrane in alternating electric field, Biophys. J. source
Not checked in the free run.
- The authors state this as an assumption: In the bioelectrorheological framework, the cell model consists of cytoplasm, membrane, and external medium simplified as homogeneous, with cytoplasm and medium considered non-viscous fluids and the membrane considered an elastic and viscous element.
- Premisecitation
The range of frequencies that results in high constant extensile stress values can be extended to include even higher frequencies by increasing the external medium conductivity.
“However, this range of frequencies that results in high constant extensile stress values can be extended to include even higher frequencies, by increasing the external medium conductivity (Table 1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [40] Fikus, 1993, Bioelectrorheological model of the cell. Analysis of the extensil deformation of cellular membrane in alternating electric field, Biophys. J. source
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- The authors state this as an assumption: To analyze extensile stress, the model of the cell is simplified to an elastic shell assumed to be homogeneous with constant volume and slightly compressible area and thickness.
- The authors state this as an assumption: Internal and external media in the extensile stress model are assumed to be isotropic, noncompressible, non-viscous liquids.
- The authors state this as an assumption: Changes in shell thickness, area, and volume (which is assumed to be zero) are used to calculate the magnitude of extensile stress caused by oscillating electric fields.
- Premisecitation
Extensile stress is dependent on the AEF's amplitude and frequency and the electric and geometric parameters of the cell system, including membrane dielectric properties and cell radius.
“Furthermore, extensile stress is dependent on the AEF’s amplitude and frequency and the electric and geometric parameters of the cell system, including membrane dielectric properties and cell radius [40].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [40] Fikus, 1993, Bioelectrorheological model of the cell. Analysis of the extensil deformation of cellular membrane in alternating electric field, Biophys. J. source
Not checked in the free run.
- The authors state this as an assumption: In the bioelectrorheological framework, the cell model consists of cytoplasm, membrane, and external medium simplified as homogeneous, with cytoplasm and medium considered non-viscous fluids and the membrane considered an elastic and viscous element.
- Premisecitation
The bioelectrorheological model can be applied to extensile mechanical stress, observed with AEFs of 0.1 to 10,000 kHz, leading to destabilization of the cell membrane and eventually electroporation.
“The bioelectrorheological model of the cell can also be applied to extensile mechanical stress, which is observed with application of AEFs with frequencies of 0.1 to 10,000 kHz, and leads to destabilization of the cell membrane and, eventually, electroporation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [40] Fikus, 1993, Bioelectrorheological model of the cell. Analysis of the extensil deformation of cellular membrane in alternating electric field, Biophys. J. source
Not checked in the free run.
- The authors state this as an assumption: In the bioelectrorheological framework, the cell model consists of cytoplasm, membrane, and external medium simplified as homogeneous, with cytoplasm and medium considered non-viscous fluids and the membrane considered an elastic and viscous element.
- Premisecitation
5-ns duration, high-intensity (50,000 V/cm) electric pulses were sufficient to open up the L-type Cav2+ channels, resulting in detectable calcium influx.
“This study concluded that 5-ns duration, high-intensity (50,000 V/cm) electric pulses were sufficient to open up the L-type Cav2+ channels, resulting in detectable calcium influx [65].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [65] Craviso, 2010, Nanosecond Electric Pulses: A Novel Stimulus for Triggering Ca2+ Influx into Chromaffin Cells Via Voltage-Gated Ca2+ Channels, Cell. Mol. Neurobiol. source
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- Premisecitation
AEFs have been shown to permeabilize cancer cell membranes in a selective and reversible manner.
“AEFs have been shown to permeabilize cancer cell membranes in a selective and reversible manner [27].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] Chang, 2018, Tumor treating fields increases membrane permeability in glioblastoma cells, Cell Death Discov. source
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- Premisecitation
Recent studies suggest that chemical and structural changes in the lipids and proteins (such as ion channels) of the membrane itself also contribute to the mechanism of action of electroporation.
“While it has been recognized for some time now that aqueous pore formation allows for increased permeability across the plasma membrane, recent studies suggest that chemical and structural changes in the lipids and proteins (such as ion channels) of the membrane itself also contribute to the mechanism of action [62].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [62] Kotnik, 2019, Membrane Electroporation and Electropermeabilization: Mechanisms and Models, Annu. Rev. Biophys. source
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- Interpretationreasoning
The resting Vm needed to reach both the first and second electroporation thresholds is lower in cancer cells than in non-cancer cells.
“The consequence of this difference is that the resting Vm needed to reach both the first and second thresholds is lower in cancer cells than in non-cancer cells.”
Quote in the paperSubstantial claim - Interpretationnone given
Significant differences in parameters (electric field intensity, electric field frequency, and duration of exposure) limit the degree to which electroporation is comparable to TTFields.
“While the electroporation model can provide further insight into how electric fields affect cancer cells and their membranes, we believe significant differences in parameters (i.e., electric field intensity, electric field frequency, and duration of exposure) limit the degree to which electroporation is comparable to TTFields.”
Quote in the paperSubstantial claim - Premisecitation
Modulation of chloride, sodium, potassium, and calcium channel activity has been found to contribute to the relatively depolarized resting Vm in cancer cells.
“Modulation of chloride, sodium, potassium, and calcium channel activity has also been found to contribute to the relatively depolarized resting Vm in cancer cells [71].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [71] Blackiston, 2009, Bioelectric controls of cell proliferation: Ion channels, membrane voltage and the cell cycle, Cell Cycle source
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- Premisecitation
Electrochemotherapy has proven effective in targeting cancer cells that are otherwise resistant to the chemotherapy being administered.
“In particular, electrochemotherapy has proven effective in targeting cancer cells that are otherwise resistant to the chemotherapy being administered [78].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [78] Frandsen, S.K., Vissing, M., and Gehl, J. (2020). A Comprehensive Review of Calcium Electroporation—A Novel Cancer Treatment Modality. Cancers, 12. source
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- Interpretationreasoning
The electroporation model does not fully explain the mechanism by which TTFields leads to cell membrane permeabilization.
“The electroporation model can be used to predict the effects of TTFields on cancer and non-cancer cells, but it does not fully explain the mechanism by which TTFields leads to cell membrane permeabilization.”
Quote in the paperSubstantial claim - Premisecitation
Cancer cells have a relatively depolarized resting Vm compared to non-cancer cells, observed in various cellular types of the brain.
“Further evidence of the relatively depolarized resting Vm of cancer cells in comparison to that of non-cancer cells has been observed in various cellular types of the brain (summarized in Table S4) [81,82,83].”
- Also stated in: § 3. Discussion · plain
“This may not be surprising given that the resting Vm of cancer cells is depolarized relative to that of non-cancer cells [28,29,30,31,73,74,75].”
Quote in the paperNot a substantial claim0 of 10 sources checked- cites [81] Hanani, 2000, Patch-clamp study of neurons and glial cells in isolated myenteric ganglia, Am. J. Physiol. Liver Physiol.
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- cites [82] Baranyi, 1993, Electrophysiological characterization of different types of neurons recorded in vivo in the motor cortex of the cat. II. Membrane parameters, action potentials, current-induced voltage responses and electrotonic structures, J. Neurophysiol. source
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- cites [83] Olsen, 2004, Mislocalization of Kir channels in malignant glia, Glia source
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- cites [28] Lobikin, 2012, Resting potential, oncogene-induced tumorigenesis, and metastasis: The bioelectric basis of cancerin vivo, Phys. Biol. source
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- cites [29] Marino, 1994, Association between Cell Membrane Potential and Breast Cancer, Tumor Biol. source
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- cites [30] Tokuoka, 1957, The membrane potential of the human cancer and related cells. I, Gan
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- cites [31] Yang, 2013, Membrane potential and cancer progression, Front. Physiol. source
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- cites [73] Iwagaki, 1989, Monitoring the effect of an anti-cancer drug on RPMI 4788 cells by a membrane potential probe, dis-C3-(5), J. Med.
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- cites [74] Gessner, 2006, BKCa Channels Activating at Resting Potential without Calcium in LNCaP Prostate Cancer Cells, J. Membr. Biol. source
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- cites [75] Ashmore, 2019, Wnts control membrane potential in mammalian cancer cells, J. Physiol. source
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- Also stated in: § 3. Discussion · plain
- Premisecitation
Alternating electric fields disrupt the plasma membrane of human glioblastoma cells.
“For example, the application of alternating electric fields has been shown to disrupt the membranes of subcellular compartments [85] as well as the plasma membrane of human glioblastoma cells [27].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] Chang, 2018, Tumor treating fields increases membrane permeability in glioblastoma cells, Cell Death Discov. source
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- Premisecitation
Modeling studies 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.
“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].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [51] Li, 2020, A Theoretical Analysis of the Effects of Tumor-Treating Electric Fields on Single Cells, Bioelectromagnetics source
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- cites [69] Li, 2020, A Theoretical Study on the Biophysical Mechanisms by Which Tumor Treating Fields Affect Tumor Cells During Mitosis, IEEE Trans. Biomed. Eng. source
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- Interpretationreasoning
The relatively depolarized resting Vm in cancer cells could explain why, compared to non-cancer cells, cancer cells are more vulnerable to both electroporation and TTFields.
“The relatively depolarized resting Vm 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).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [67] Jourabchi, 2014, Irreversible electroporation (NanoKnife) in cancer treatment, Gastrointest. Interv. source
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- cites [69] Li, 2020, A Theoretical Study on the Biophysical Mechanisms by Which Tumor Treating Fields Affect Tumor Cells During Mitosis, IEEE Trans. Biomed. Eng. source
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- Premisecitation
Alternating electric fields disrupt the membranes of subcellular compartments.
“For example, the application of alternating electric fields has been shown to disrupt the membranes of subcellular compartments [85] as well as the plasma membrane of human glioblastoma cells [27].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [85] Shteingauz, 2018, AMPK-dependent autophagy upregulation serves as a survival mechanism in response to Tumor Treating Fields (TTFields), Cell Death Dis. source
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- Interpretationnone given
The electroporation model can be used to predict the effects of TTFields on cancer and non-cancer cells.
“The electroporation model can be used to predict the effects of TTFields on cancer and non-cancer cells, but it does not fully explain the mechanism by which TTFields leads to cell membrane permeabilization.”
Quote in the paperNot a substantial claim - Interpretationnone given
The functionally therapeutic ranges of TTFields' frequency (100-500 kHz) and field strength (1-4 V/cm) often do not overlap with the proposed field strengths and frequencies of the Cav2+, bioelectrorheological, and electroporation models.
“However, as reviewed above, the functionally therapeutic ranges of TTFields’ frequency (100–500 kHz) and field strength (1–4 V/cm) often do not overlap with the proposed field strengths and frequencies of the Cav2+, bioelectrorheological, and electroporation models.”
Quote in the paperSubstantial claim - Interpretationnone given
The observed versus theoretical discrepancies may stem from most computational modeling studies being based upon single cells in isolation.
“The resolution of the observed versus theoretical discrepancies may stem from the fact that most computational modeling studies are based upon single cells in isolation.”
Quote in the paperSubstantial claim- Rests on an assumption: Most computational modeling studies are based upon single cells in isolation.
- Interpretationcitation
Membrane distortions predicted by the bioelectrorheological model are likely another feature of TTFields' actions.
“For example, TTFields have been reported to activate Cav2+ channels [46], membrane distortions predicted by the bioelectrorheological model are likely another feature of TTFields’ actions [40], and membrane fenestration is a hallmark of reversible electroporation [62].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Fikus, 1993, Bioelectrorheological model of the cell. Analysis of the extensil deformation of cellular membrane in alternating electric field, Biophys. J. source
Not checked in the free run.
- Interpretationcitation
The unexpectedly high field strengths achieved in regions between closely packed cells may remove the obstacle of electric field strength being insufficient for bioelectrorheological and electroporative processes to explain the empirical observation of membrane fenestration due to TTFields.
“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].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] Chang, 2018, Tumor treating fields increases membrane permeability in glioblastoma cells, Cell Death Discov. source
Not checked in the free run.
- Interpretationreasoning
The explanation of AEF-induced alteration of membrane function will most likely consist of a combination of the bioelectrorheological and electroporation models.
“Rather, the explanation of AEF-induced alteration of membrane function will most likely consist of a combination of the bioelectrorheological and electroporation models.”
Quote in the paperSubstantial claim - Interpretationreasoning
Augmentation of field strength in adjacent membrane regions of densely packed cells may lead to values concordant with either the bioelectrorheological or electroporation models.
“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.”
Quote in the paperSubstantial claim - Interpretationreasoning
The effects of AEF on membrane function in cancers is insufficiently explained by the impact on voltage-gated calcium channels alone.
“The effects of AEF on membrane function in cancers is insufficiently explained by the impact on voltage-gated calcium channels alone; however, alterations in channel function might serve as a biomarker of AEF action.”
Quote in the paperSubstantial claim
- May combine two claims. 45
- Classified as probably not a substantial claim. 21
May combine two claims.
PremisecitationIn newly diagnosed glioblastoma, 200 kHz TTFields combined with adjuvant temozolomide prolonged median overall survival by 4.9 months and median progression-free survival by 2.7 months compared with adjuvant temozolomide alone.
“Based on the results of a phase III clinical trial that showed 200 kHz TTFields in combination with adjuvant temozolomide chemotherapy prolonged the median overall survival (OS) in newly diagnosed GBM patients by 4.9 months (and prolonged median progression-free survival [PFS] by 2.7 months) compared to adjuvant temozolomide alone”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [11] Stupp, 2015, Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs. Temozolomide Alone for Glioblastoma, JAMA source
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- cites [12] Stupp, 2017, Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs. Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma, JAMA source
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May combine two claims.
PremisecitationTTFields-induced membrane effects occur in cancer cells but not in non-cancer cells.
“Such effects were shown to occur in cancer cells but not in non-cancer cells [27].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] Chang, 2018, Tumor treating fields increases membrane permeability in glioblastoma cells, Cell Death Discov. source
Not checked in the free run.
May combine two claims.
PremisecitationTTFields-induced mitotic spindle perturbations lead to abnormal chromosomal segregation, mitotic cell death, and perhaps apoptosis from cells that are able to exit mitosis.
“Such perturbations lead to abnormal chromosomal segregation, mitotic cell death, and perhaps apoptosis from cells that are able to exit mitosis [8,9,19].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [8] Giladi, 2016, Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells, Sci. Rep. source
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- cites [9] Kirson, 2004, Disruption of Cancer Cell Replication by Alternating Electric Fields, Cancer Res. source
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- cites [19] Tuszynski, J.A., Wenger, C., Friesen, D.E., and Preto, J. (2016). An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields. Int. J. Environ. Res. Public Heal., 13. source
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCancer cells are more deformable compared to non-cancer cells because of altered membrane composition, and their responsiveness to fluid shear stress differs from that of non-cancer cells.
“Cancer cells are more deformable compared to non-cancer cells because of their altered membrane composition; consequently, cancer cells’ responsiveness to fluid shear stress has been reported to be different from that of non-cancer cells [32,33,34].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [32] Barnes, J.M., Nauseef, J.T., and Henry, M.D. (2012). Resistance to Fluid Shear Stress Is a Conserved Biophysical Property of Malignant Cells. PLoS ONE, 7. source
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- cites [33] Huang, 2018, Fluid shear stress and tumor metastasis, Am. J. Cancer Res.
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- cites [34] Sok, 2002, Cell membrane fluidity and prognosis of lung cancer, Ann. Thorac. Surg. source
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May combine two claims.
PremisecitationCancer cells have alterations in ion channel expression, membrane distribution, and function.
“There are also alterations in ion channel expression, membrane distribution, and function in cancer cells, which indicates how ion channel changes could serve as biomarkers of tumor progression [35].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Lastraioli, 2015, Ion channel expression as promising cancer biomarker, Biochim. Biophys. Acta (BBA) Biomembr. source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAmplification of the applied TTFields signal can be generated at the cleavage furrow during cell division.
“Previous simulation studies [36] have shown that amplification of the applied signal could be generated at the cleavage furrow during cell division.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36] Wenger, 2015, Modeling Tumor Treating Fields (TTFields) application in single cells during metaphase and telophase, Proceedings of the 2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC)
Not checked in the free run.
May combine two claims.
PremisecitationIn a single-arm phase II trial of 150 kHz TTFields plus pemetrexed and platinum-based chemotherapy in malignant pleural mesothelioma, median overall survival and progression-free survival were 18.2 months and 7.6 months, respectively, compared with historical controls of 12.1 months and 5.7 months.
“In this single-arm phase II clinical trial, the median OS and PFS were 18.2 months and 7.6 months, respectively [13], compared to corresponding historical controls of 12.1 months and 5.7 months from a 2003 phase III clinical trial evaluating pemetrexed in combination with cisplatin in MPM [14].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [13] Ceresoli, 2019, Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): A multicentre, single-arm phase 2 trial, Lancet Oncol. source
Not checked in the free run.
- cites [14] Vogelzang, 2003, Phase III Study of Pemetrexed in Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural Mesothelioma, J. Clin. Oncol. source
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May combine two claims.
InterpretationcitationNeuhaus et al. showed correlation of AEF effects on Cav1.2 channels with previously reported TTFields effects, but not causation.
“In summary, Neuhaus et al. showed correlation of AEF effects on Cav1.2 channels with previously reported TTFields’ effects, but not causation, probably due to low AEF field strength and use of a single-direction electric field [46].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46] Neuhaus, E., Zirjacks, L., Ganser, K., Klumpp, L., Schüler, U., Zips, D., Eckert, F., and Huber, S.M. (2019). Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells. Cancers, 11. source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationTwo theories have been proposed for how electromagnetic fields modulate Cav2+ channels: depolarization of the cell membrane, and direct action on the charged residues in the voltage-sensing S4 segment adjacent to the pore.
“To answer the first question, two theories have been proposed for how electromagnetic fields modulate Cav2+ channels: (1) by depolarization of the cell membrane, which is typically employed in mechanism of action explanations of voltage-gated ion channels such as Nav+, Kv+, and Cav2+ [48] and (2) by direct action on the charged residues in the voltage-sensing S4 segment adjacent to the pore that”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [48] Pall, 2013, Electromagnetic fields act via activation of voltage-gated calcium channels to produce beneficial or adverse effects, J. Cell. Mol. Med. source
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- cites [49] Catterall, 2000, Structure and Regulation of Voltage-Gated Ca2+Channels, Annu. Rev. Cell Dev. Biol. source
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- cites [50] Catterall, 2011, Voltage-Gated Calcium Channels, Cold Spring Harb. Perspect. Biol. source
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May combine two claims.
PremisecitationThe bioelectrorheological model demonstrates the relationship between AEFs, shape deformations, and membrane destabilization, which can contribute to electroporation and other electric field-induced cell phenomena including electrofusion and electro-destruction.
“The bioelectrorheological model of the cell was proposed and has been expanded upon through a series of manuscripts by Pawlowski et al. [40,53,54,55,56,57] (Figure 3B). This model demonstrates the relationship between AEFs, shape deformations, and membrane destabilization, which can contribute to electroporation and other electric field-induced cell phenomena including electrofusion and electro-d”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [40] Fikus, 1993, Bioelectrorheological model of the cell. Analysis of the extensil deformation of cellular membrane in alternating electric field, Biophys. J. source
Not checked in the free run.
- cites [53] Pawlowski, 1989, Bioelectrorheological model of the cell Analysis of stresses and deformations, J. Biol.
Not checked in the free run.
- cites [54] Fikus, 1989, Bioelectrorheological model of the cell. 2. Analysis of creep and its experimental verification, J. Theor. Biol. source
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- cites [55] Szutowicz, 1993, Bioelectrorheological model of the cell. 5. Electrodestruction of cellular membrane in alternating electric field, Biophys. J. source
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- cites [56] Pawlowski, 1996, Bioelectrorheological model of the cell. VI. Experimental verification of the rheological model of cytoplasmic membrane, Biophys. J. source
Not checked in the free run.
- cites [57] Poznanski, 1992, Bioelectrorheological model of the cell. Viscoelastic shear deformation of the membrane, Biophys. J. source
Not checked in the free run.
- The authors state this as an assumption: In the bioelectrorheological framework, the cell model consists of cytoplasm, membrane, and external medium simplified as homogeneous, with cytoplasm and medium considered non-viscous fluids and the membrane considered an elastic and viscous element.
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone givenAEFs may affect cellular membrane permeability by imposing an EMF gradient that forces voltage-gated ion channels to adopt an open state and thus cause increased ionic and molecular permeability.
“First, AEFs may affect cellular membrane permeability by imposing an EMF gradient that forces voltage-gated ion channels to adopt an “open” state and thus cause increased ionic and molecular permeability (Figure 3A and Table S1).”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation200 kHz AEFs at 1 V/cm (TTFields) affected a voltage-gated calcium channel (Cav1.2) in T98 human glioblastoma cells and produced apoptosis as well as G1 or S phase cell cycle arrest, breakdown of the inner mitochondrial membrane potential, and DNA degradation.
“For example, using several empirical techniques, Neuhaus et al. [46] showed that 200 kHz AEFs at 1 V/cm (i.e., TTFields) affected a voltage-gated calcium channel (Cav1.2) in T98 human glioblastoma cells and produced apoptosis as well as G1 or S phase cell cycle arrest, breakdown of the inner mitochondrial membrane potential, and DNA degradation [46].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [46] Neuhaus, E., Zirjacks, L., Ganser, K., Klumpp, L., Schüler, U., Zips, D., Eckert, F., and Huber, S.M. (2019). Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells. Cancers, 11. source
Not checked in the free run.
May combine two claims.
InterpretationreasoningEven if TTFields open Cav2+ channels, the effect would be secondary to the effect of the pores found by Chang et al.; complete equalization of all ion differentials across the cell membrane would occur rapidly and fully depolarize the cell, making Ca2+ conductance effects superfluous.
“Further, we conclude that even if TTFields open Cav2+ channels, the effect would be secondary to the effect of the pores found by Chang et al. [27]. The size of the pores compared to ion channel diameters and their presumed non-ion-specificity implies that, by the Nernst and Goldman equations [52], complete equalization of all ion differentials across the cell membrane would occur rapidly and”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [27] Chang, 2018, Tumor treating fields increases membrane permeability in glioblastoma cells, Cell Death Discov. source
Not checked in the free run.
- cites [52] Ermentrout, B.D.H.T. (2010). Mathematical Foundations of Neuroscience, Springer. source
Not checked in the free run.
- The authors state this as an assumption: TTFields act on voltage-gated Cav2+ channels.
May combine two claims.
Interpretationown dataImportant amplification of the TTFields signal at TTFields frequencies could occur at the membrane pore or channel level, or in the intercellular spaces between confluent cells.
“Instead, we demonstrate that important amplification of the signal at TTFields frequencies could occur at the membrane pore or channel level, or in the intercellular spaces between confluent cells.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationThe low efficacy in Neuhaus et al. is probably due to the lower field strength (1 V/cm) compared to the 2-3 V/cm needed for higher efficacy, and to the use of a single-direction electric field.
“The low efficacy is probably due to the lower field strength (1 V/cm in Neuhaus et al. [46]) compared to what Kirson et al. [47] showed is needed for higher efficacy: 2–3 V/cm [47]. The latter setting resulted in a reduction in cancer cell number [47]. Neuhaus et al. also did not change the AEF direction with respect to the cells, which significantly increases efficacy as demonstrated by Kirson et”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [46] Neuhaus, E., Zirjacks, L., Ganser, K., Klumpp, L., Schüler, U., Zips, D., Eckert, F., and Huber, S.M. (2019). Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells. Cancers, 11. source
Not checked in the free run.
- cites [47] Kirson, 2007, Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors, Proc. Natl. Acad. Sci. USA source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationLi et al. predicted that TTFields depolarize the cell membrane by 10-17%, which may be enough to open membrane Cav2+ channels and, at TTFields frequency, would likely freeze the channels in an open state.
“Li et al. [51] predicted that TTFields depolarize the cell membrane by 10-17%, which may be enough to open membrane Cav2+ channels [51] and, at TTFields’ frequency, would likely ‘freeze’ the channels in an open state.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [51] Li, 2020, A Theoretical Analysis of the Effects of Tumor-Treating Electric Fields on Single Cells, Bioelectromagnetics source
Not checked in the free run.
May combine two claims.
PremisecitationHeat energy leads to membrane destabilization, which in turn leads to an increased susceptibility to electroporation.
“This is significant because heat energy leads to membrane destabilization, which in turn leads to an increased susceptibility to electroporation [55].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [55] Szutowicz, 1993, Bioelectrorheological model of the cell. 5. Electrodestruction of cellular membrane in alternating electric field, Biophys. J. source
Not checked in the free run.
May combine two claims.
PremisecitationApplication of AEFs causes shear stress or extensile mechanical stress to act on the cell membrane, disrupting its integrity and stability.
“The application of AEFs causes different types of stress to act on the cell membrane, thereby disrupting its integrity and stability. Based on electrical and geometric parameters of the system, cells either experience shear stress or extensile mechanical stress.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [53] Pawlowski, 1989, Bioelectrorheological model of the cell Analysis of stresses and deformations, J. Biol.
Not checked in the free run.
- cites [57] Poznanski, 1992, Bioelectrorheological model of the cell. Viscoelastic shear deformation of the membrane, Biophys. J. source
Not checked in the free run.
- The authors state this as an assumption: In the bioelectrorheological framework, the cell model consists of cytoplasm, membrane, and external medium simplified as homogeneous, with cytoplasm and medium considered non-viscous fluids and the membrane considered an elastic and viscous element.
May combine two claims.
PremisecitationIn N. crassa, the maximum value of extensile stress was modeled as a function of electric field frequency (0.1 to 100,000 kHz) using an electric field strength of 250 V/cm, which is two orders of magnitude greater than the field strength of TTFields (1-4 V/cm).
“In N. crassa, the maximum value of extensile stress was modeled as a function of electric field frequency (ranging from 0.1 to 100,000 kHz) using an electric field strength (E) of 250 V/cm [40], which is two orders of magnitude greater than the field strength of TTFields (i.e., 1–4 V/cm).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Fikus, 1993, Bioelectrorheological model of the cell. Analysis of the extensil deformation of cellular membrane in alternating electric field, Biophys. J. source
Not checked in the free run.
- The authors state this as an assumption: To analyze extensile stress, the model of the cell is simplified to an elastic shell assumed to be homogeneous with constant volume and slightly compressible area and thickness.
- The authors state this as an assumption: Internal and external media in the extensile stress model are assumed to be isotropic, noncompressible, non-viscous liquids.
- The authors state this as an assumption: Changes in shell thickness, area, and volume (which is assumed to be zero) are used to calculate the magnitude of extensile stress caused by oscillating electric fields.
May combine two claims.
PremisecitationSusceptibility to electroporation increased with increasing AEF frequency, but the extent of increased susceptibility became attenuated at higher conductivities of the external medium.
“Although s(p) increased with increasing AEF frequency, it was found that the extent of increased susceptibility became attenuated at higher conductivities of the external medium (Table 2) [55].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [55] Szutowicz, 1993, Bioelectrorheological model of the cell. 5. Electrodestruction of cellular membrane in alternating electric field, Biophys. J. source
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May combine two claims.
PremisecitationExtensile stress is influenced by membrane area and thickness as well as position on the membrane, and reaches maximum values at the poles and high values at the equator of the cell.
“It is influenced by membrane area and thickness as well as position on the membrane [40]. Stress which is calculated using Maxwell-Wagner polarization, Maxwell stress, mechanical normal, and tangential stress reaches maximum values at the poles and high values at the equator of the cell [40].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [40] Fikus, 1993, Bioelectrorheological model of the cell. Analysis of the extensil deformation of cellular membrane in alternating electric field, Biophys. J. source
Not checked in the free run.
- The authors state this as an assumption: In the bioelectrorheological framework, the cell model consists of cytoplasm, membrane, and external medium simplified as homogeneous, with cytoplasm and medium considered non-viscous fluids and the membrane considered an elastic and viscous element.
May combine two claims.
PremisecitationThe deformations observed in N. crassa were reversible and non-damaging, similar to the induction of membrane fenestrae by TTFields.
“The deformations observed were reversible and non-damaging, similar to the induction of membrane fenestrae by TTFields [27,53].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [27] Chang, 2018, Tumor treating fields increases membrane permeability in glioblastoma cells, Cell Death Discov. source
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- cites [53] Pawlowski, 1989, Bioelectrorheological model of the cell Analysis of stresses and deformations, J. Biol.
Not checked in the free run.
May combine two claims.
PremisecitationPawlowski and colleagues found a threshold frequency at which cell deformations occur, dependent on cell and membrane properties; shear stress increased with cell radius, decreased with external medium conductivity, and increased with membrane conductivity.
“Consequently, cell deformations were predicted based on electric field frequency; frequencies in the range of 1 to 1,000,000 kHz were tested; these evaluations revealed a threshold frequency at which cell deformations occur, dependent on the aforementioned properties [53]. Shear stress acting on the membrane increased with cell radius, decreased with external medium conductivity, and increased”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] Pawlowski, 1989, Bioelectrorheological model of the cell Analysis of stresses and deformations, J. Biol.
Not checked in the free run.
- The authors state this as an assumption: In the bioelectrorheological framework, the cell model consists of cytoplasm, membrane, and external medium simplified as homogeneous, with cytoplasm and medium considered non-viscous fluids and the membrane considered an elastic and viscous element.
May combine two claims.
PremisecitationHeat energy increases with increasing frequency and reaches maximal values at frequency ranges where TTFields have optimal anti-cancer efficacy, such as 200 kHz for glioblastoma and 150 kHz for pleural malignant mesothelioma.
“Heat energy increases with increasing frequency and reaches maximal values at frequency ranges where TTFields have optimal anti-cancer efficacy (e.g., 200 kHz for glioblastoma and 150 kHz for pleural malignant mesothelioma [12,13,59]).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [12] Stupp, 2017, Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs. Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma, JAMA source
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- cites [13] Ceresoli, 2019, Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): A multicentre, single-arm phase 2 trial, Lancet Oncol. source
Not checked in the free run.
- cites [59] Porat, Y., Giladi, M., Schneiderman, R.S., Blat, R., Shteingauz, A., Zeevi, E., Munster, M., Voloshin, T., Kaynan, N., and Tal, O. (2017). Determining the Optimal Inhibitory Frequency for Cancerous Cells Using Tumor Treating Fields (TTFields). J. Vis. Exp., e55820. source
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PremisecitationSusceptibility to electro-destruction reaches a maximum value at 100 kHz, which is within the range of TTFields frequencies (100-500 kHz), and membrane viscosity decreases with increasing frequency in a sigmoidal fashion, reaching minimum values at 100 kHz.
“However, it is important to note that susceptibility to electro-destruction reaches a maximum value at 100 kHz (which is within the range of TTFields frequencies (100–500 kHz)), and that membrane viscosity decreases with increasing frequency in a sigmoidal fashion, reaching minimum values at 100 kHz [55].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [55] Szutowicz, 1993, Bioelectrorheological model of the cell. 5. Electrodestruction of cellular membrane in alternating electric field, Biophys. J. source
Not checked in the free run.
May combine two claims.
InterpretationcitationExternal medium conductivity and electric field frequency have a significant influence on the magnitude of stress experienced by the cell, and therefore its membrane's stability.
“Thus, external medium conductivity and electric field frequency have a significant influence on the magnitude of stress experienced by the cell, and therefore its membrane’s stability.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMaximum extensile stress remains constantly high at low AEF frequencies and decreases in a sigmoidal fashion at higher frequencies.
“A graph of these results revealed that the maximum extensile stress remains constantly high at low AEF frequencies, and decreases in a sigmoidal fashion at higher frequencies [40].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [40] Fikus, 1993, Bioelectrorheological model of the cell. Analysis of the extensil deformation of cellular membrane in alternating electric field, Biophys. J. source
Not checked in the free run.
- The authors state this as an assumption: To analyze extensile stress, the model of the cell is simplified to an elastic shell assumed to be homogeneous with constant volume and slightly compressible area and thickness.
- The authors state this as an assumption: Internal and external media in the extensile stress model are assumed to be isotropic, noncompressible, non-viscous liquids.
- The authors state this as an assumption: Changes in shell thickness, area, and volume (which is assumed to be zero) are used to calculate the magnitude of extensile stress caused by oscillating electric fields.
May combine two claims.
PremisecitationAfter the first threshold is surpassed, the Vm depolarizes the membrane sufficiently to trigger the formation of aqueous pores and stimulate other voltage-dependent processes such as ion channel activation and cytoskeletal disruption.
“After the first threshold is surpassed, it is thought that the Vm depolarizes the membrane sufficiently to trigger the formation of aqueous pores and stimulate other voltage-dependent processes such as ion channel activation and cytoskeletal disruption [62,65].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [62] Kotnik, 2019, Membrane Electroporation and Electropermeabilization: Mechanisms and Models, Annu. Rev. Biophys. source
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- cites [65] Craviso, 2010, Nanosecond Electric Pulses: A Novel Stimulus for Triggering Ca2+ Influx into Chromaffin Cells Via Voltage-Gated Ca2+ Channels, Cell. Mol. Neurobiol. source
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PremisecitationWhen both DC and AC pulses are applied together at their optimal settings, which involves 40 kHz frequency for the AC component, both transfection efficiency and cell survivability have been shown to increase.
“When both kinds of pulses (DC and AC) are applied together at their optimal settings, which involves 40 kHz frequency for the AC component, both transfection efficiency and cell survivability have been shown to increase [61].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [61] Chang, 1989, Cell poration and cell fusion using an oscillating electric field, Biophys. J. source
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PremisecitationThe depolarized resting Vm 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.
“The depolarized resting Vm 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].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [70] Kinnunen, 2008, Membranes: A meeting point for lipids, proteins and therapies, J. Cell. Mol. Med. source
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PremisecitationElectroporation pulses can range from nanoseconds to milliseconds in duration and tend to form aqueous pores in the plasma membrane that are on the order of ~1 nm in radius.
“Electroporation pulses can range from nanoseconds to milliseconds in duration and tend to form aqueous pores in the plasma membrane that are on the order of ~1 nm in radius [60,62,63,64].”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [60] Son, 2014, Basic Features of a Cell Electroporation Model: Illustrative Behavior for Two Very Different Pulses, J. Membr. Biol. source
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- cites [62] Kotnik, 2019, Membrane Electroporation and Electropermeabilization: Mechanisms and Models, Annu. Rev. Biophys. source
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- cites [63] Burke, 2017, Nanosecond pulsed electric fields depolarize transmembrane potential via voltage-gated K+, Ca2+ and TRPM8 channels in U87 glioblastoma cells, Biochim. Biophys. Acta (BBA) Biomembr. source
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- cites [64] Krassowska, 2007, Modeling Electroporation in a Single Cell, Biophys. J. source
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May combine two claims.
PremisecitationAt electric field strengths in the 50-200 V/cm range, electroporation of endothelial cells is possible, and imaging revealed significant, reversible disruption of interphase microtubules and actin filaments.
“To better understand the effects that electroporation can have on the cell cytoskeleton, Kanthou and colleagues studied endothelial cells with fluorescence imaging and found that at electric field strengths in the 50–200 V/cm range, electroporation of endothelial cells is not only possible, but imaging also revealed significant, reversible disruption of interphase microtubules and actin filaments”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [66] Kanthou, 2006, The endothelial cytoskeleton as a target of electroporation-based therapies, Mol. Cancer source
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PremisecitationVarious 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.
“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].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [67] Jourabchi, 2014, Irreversible electroporation (NanoKnife) in cancer treatment, Gastrointest. Interv. source
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- cites [68] De Vleeschouwer, S. (2017). Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part III: Irre-versible Electroporation and High-Frequency Irreversible Electroporation for the Eradication of Glioblastoma. Glioblastoma, Codon Publications.
Not checked in the free run.
May combine two claims.
PremisecitationThe Vm 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 Vm of −70 mV whereas post-mitotic cancer cells achieve a resting Vm of −25 mV.
“The Vm 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 Vm of −70 mV whereas post-mitotic cancer cells achieve a resting Vm of −25 mV [51,69].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [51] Li, 2020, A Theoretical Analysis of the Effects of Tumor-Treating Electric Fields on Single Cells, Bioelectromagnetics source
Not checked in the free run.
- cites [69] Li, 2020, A Theoretical Study on the Biophysical Mechanisms by Which Tumor Treating Fields Affect Tumor Cells During Mitosis, IEEE Trans. Biomed. Eng. source
Not checked in the free run.
May combine two claims.
PremisecitationThe critical Vm is cell-specific and is the transmembrane potential that destabilizes the membrane beyond repair (irreversible electroporation), resulting in cell death.
“The critical Vm is cell-specific and is the transmembrane potential that destabilizes the membrane beyond repair (i.e., irreversible electroporation), resulting in cell death [41].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [41] Sarnago, 2019, Histopathological and Ultrastructural Changes after Electroporation in Pig Liver Using Parallel-Plate Electrodes and High-Performance Generator, Sci. Rep. source
Not checked in the free run.
May combine two claims.
PremisecitationBoth DC and AC electroporation are believed to cause a dielectric breakdown of the cell; the oscillating nature of AC electroporation is thought to provoke structural fatigue of the membrane, comparable to the extensile stress proposed in the bioelectrorheological model.
“Both types of electroporation are believed to cause a dielectric breakdown of the cell. However, the oscillating nature of AC electroporation is thought to provoke structural fatigue of the membrane [61], comparable to the extensile stress proposed in the bioelectrorheological model [40,53,54,55,56,57].”
Quote in the paperNot a substantial claim0 of 7 sources checked- cites [61] Chang, 1989, Cell poration and cell fusion using an oscillating electric field, Biophys. J. source
Not checked in the free run.
- cites [40] Fikus, 1993, Bioelectrorheological model of the cell. Analysis of the extensil deformation of cellular membrane in alternating electric field, Biophys. J. source
Not checked in the free run.
- cites [53] Pawlowski, 1989, Bioelectrorheological model of the cell Analysis of stresses and deformations, J. Biol.
Not checked in the free run.
- cites [54] Fikus, 1989, Bioelectrorheological model of the cell. 2. Analysis of creep and its experimental verification, J. Theor. Biol. source
Not checked in the free run.
- cites [55] Szutowicz, 1993, Bioelectrorheological model of the cell. 5. Electrodestruction of cellular membrane in alternating electric field, Biophys. J. source
Not checked in the free run.
- cites [56] Pawlowski, 1996, Bioelectrorheological model of the cell. VI. Experimental verification of the rheological model of cytoplasmic membrane, Biophys. J. source
Not checked in the free run.
- cites [57] Poznanski, 1992, Bioelectrorheological model of the cell. Viscoelastic shear deformation of the membrane, Biophys. J. source
Not checked in the free run.
May combine two claims.
PremisecitationThere are two thresholds for electroporation that are not universal but particular to the parameters being used (cell type/size, membrane curvature, exposure time, temperature, transported molecule, and osmotic pressure): the induced transmembrane potential needed to cause a detectable increase in membrane permeability, and the critical Vm at which reversible electroporation becomes irreversible.
“An important component of this proposed mechanism, by which altering the plasma membrane through electric pulses leads to increased permeability, is that there are two “thresholds” which are not universal but rather particular to the parameters being used (i.e., cell type/size, membrane curvature, exposure time, temperature, transported molecule, and osmotic pressure) [62]. The first threshold is”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [62] Kotnik, 2019, Membrane Electroporation and Electropermeabilization: Mechanisms and Models, Annu. Rev. Biophys. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTTFields have been reported to activate Cav2+ channels.
“For example, TTFields have been reported to activate Cav2+ channels [46], membrane distortions predicted by the bioelectrorheological model are likely another feature of TTFields’ actions [40], and membrane fenestration is a hallmark of reversible electroporation [62].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46] Neuhaus, E., Zirjacks, L., Ganser, K., Klumpp, L., Schüler, U., Zips, D., Eckert, F., and Huber, S.M. (2019). Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells. Cancers, 11. source
Not checked in the free run.
May combine two claims.
PremisecitationElectrochemotherapy damages cancer cells by porating the membrane so that chemotherapeutic agents can more easily permeate into the cell, resulting in a synergistic effect.
“Similarly, electrochemotherapy aims to damage cancer cells, but it does so by porating the membrane so that chemotherapeutic agents can more easily permeate into the cell, resulting in a synergistic effect [79].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [79] Jaroszeski, 1997, Electrochemotherapy: An emerging drug delivery method for the treatment of cancer, Adv. Drug Deliv. Rev. source
Not checked in the free run.
May combine two claims.
InterpretationcitationIon channel activation and ion influx, and perhaps other effects such as cytoskeleton damage, can be used as biomarkers of responsiveness to TTFields.
“The results from electroporation studies further support that ion channel activation and ion influx, and perhaps other effects such as cytoskeleton damage, can be used as biomarkers of responsiveness to TTFields, given that these phenomena are observed after exposure to electric fields [27,46,62,65].”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [27] Chang, 2018, Tumor treating fields increases membrane permeability in glioblastoma cells, Cell Death Discov. source
Not checked in the free run.
- cites [46] Neuhaus, E., Zirjacks, L., Ganser, K., Klumpp, L., Schüler, U., Zips, D., Eckert, F., and Huber, S.M. (2019). Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells. Cancers, 11. source
Not checked in the free run.
- cites [62] Kotnik, 2019, Membrane Electroporation and Electropermeabilization: Mechanisms and Models, Annu. Rev. Biophys. source
Not checked in the free run.
- cites [65] Craviso, 2010, Nanosecond Electric Pulses: A Novel Stimulus for Triggering Ca2+ Influx into Chromaffin Cells Via Voltage-Gated Ca2+ Channels, Cell. Mol. Neurobiol. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMitotic disruption by exogenously imposed electric fields has been reported.
“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.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Giladi, 2016, Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells, Sci. Rep. source
Not checked in the free run.
Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).
PremisecitationCancer cells may be more sensitive to electroporation because they are less equipped to repair and restore the plasma membrane after damage.
“A study by Frandsen and colleagues investigated the mechanisms of calcium electroporation, leading the authors to hypothesize that cancer cells may be more sensitive to electroporation because they are less equipped to repair and restore the plasma membrane after damage [78,80].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [78] Frandsen, S.K., Vissing, M., and Gehl, J. (2020). A Comprehensive Review of Calcium Electroporation—A Novel Cancer Treatment Modality. Cancers, 12. source
Not checked in the free run.
- cites [80] Frandsen, 2016, Difference in Membrane Repair Capacity Between Cancer Cell Lines and a Normal Cell Line, J. Membr. Biol. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDigitalis, a sodium-potassium ATPase inhibitor, has been shown to limit the proliferation of human breast cancer cells.
“For example, digitalis, a sodium-potassium ATPase inhibitor, has been shown to limit the proliferation of human breast cancer cells [72].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [72] Kometiani, 2004, Digitalis-Induced Signaling by Na+/K+-ATPase in Human Breast Cancer Cells, Mol. Pharm. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCalcium electroporation is thought to work by the same mechanism as electrochemotherapy and uses calcium because of its role as a second messenger for various processes resulting in cell death.
“For instance, calcium electroporation is thought to work by the same mechanism as electrochemotherapy, and it uses calcium because of its role as a second messenger for various processes resulting in cell death [78].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [78] Frandsen, S.K., Vissing, M., and Gehl, J. (2020). A Comprehensive Review of Calcium Electroporation—A Novel Cancer Treatment Modality. Cancers, 12. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe standard theory proposes that TTFields disrupt the mitotic spindle in actively dividing cells, leading to aberrant cellular division and eventual cellular death.
“The standard theory proposes a disruption of the mitotic spindle by TTFields in actively dividing cells, thereby leading to aberrant cellular division and eventual cellular death [8,84].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [8] Giladi, 2016, Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells, Sci. Rep. source
Not checked in the free run.
- cites [84] Voloshin, T., Schneiderman, R.S., Volodin, A., Shamir, R.R., Kaynan, N., Zeevi, E., Koren, L., Klein-Goldberg, A., Paz, R., and Giladi, M. (2020). Tumor Treating Fields (TTFields) Hinder Cancer Cell Motility through Regulation of Microtubule and Acting Dynamics. Cancers, 12. source
Not checked in the free run.
May combine two claims.
PremisecitationTTFields may have effects on DNA damage response and replication stress, ER stress, membrane permeability, autophagy, and immune response.
“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].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] Karanam, N.K., and Story, M.D. (2020). An overview of potential novel mechanisms of action underlying Tumor Treating Fields-induced cancer cell death and their clinical implications. Int. J. Radiat. Biol., 1–11.
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationcitationThe standard theory of how TTFields work requires further elaboration.
“Recent investigations [27] have shown that the standard theory of how TTFields work [8] requires further elaboration.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [27] Chang, 2018, Tumor treating fields increases membrane permeability in glioblastoma cells, Cell Death Discov. source
Not checked in the free run.
- cites [8] Giladi, 2016, Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells, Sci. Rep. source
Not checked in the free run.
- Rests on an assumption: Mitotic spindles are not the only biological structures that possess intrinsic dipole moments.
- Rests on an assumption: DNA possesses intrinsic dipole moments.
May combine two claims.
InterpretationcitationEach of the three models (voltage-gated ion channels, bioelectrorheological, electroporation) is related to and possesses features consistent with the reported effects of TTFields.
“Each model is related to and possesses features that are consistent with the reported effects of TTFields.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
InterpretationcitationThe membrane potential could serve as an important read-out to monitor in studies of TTFields.
“Certainly, the recent work of Li et al. [51,69] suggests that the membrane potential could serve as an important read-out to monitor in studies of TTFields.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [51] Li, 2020, A Theoretical Analysis of the Effects of Tumor-Treating Electric Fields on Single Cells, Bioelectromagnetics source
Not checked in the free run.
- cites [69] Li, 2020, A Theoretical Study on the Biophysical Mechanisms by Which Tumor Treating Fields Affect Tumor Cells During Mitosis, IEEE Trans. Biomed. Eng. source
Not checked in the free run.
May combine two claims.
PremisecitationPTEN is involved in maintaining mitotic spindle architecture and promoting chromosome alignment and segregation.
“PTEN is involved in maintaining mitotic spindle architecture and promoting chromosome alignment and segregation, functions overlapping with the postulated mechanism of action of TTFields [8,91,92].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [8] Giladi, 2016, Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells, Sci. Rep. source
Not checked in the free run.
- cites [91] Hou, 2017, PTEN in the maintenance of genome integrity: From DNA replication to chromosome segregation, BioEssays source
Not checked in the free run.
- cites [92] Kessler, 2018, Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition, Cell Death Discov. source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable), S4 (based).
InterpretationreasoningThese findings could be exploited to enhance drug delivery to cancer cells shielded by the blood-brain barrier.
“These findings could be exploited to enhance drug delivery to cancer cells shielded by the blood–brain barrier.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningLoss-of-function mutations in PTEN could potentiate the inhibition of microtubule polymerization and mitotic spindle apparatus assembly known to result from TTFields exposure.
“Thus, it is possible that loss-of-function mutations in PTEN could potentiate the inhibition of microtubule polymerization and mitotic spindle apparatus assembly that are known to result from TTFields exposure.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMembrane fenestration is a hallmark of reversible electroporation.
“For example, TTFields have been reported to activate Cav2+ channels [46], membrane distortions predicted by the bioelectrorheological model are likely another feature of TTFields’ actions [40], and membrane fenestration is a hallmark of reversible electroporation [62].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [62] Kotnik, 2019, Membrane Electroporation and Electropermeabilization: Mechanisms and Models, Annu. Rev. Biophys. source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe same phenomenon (high field strengths in contact regions) provides an explanation for TTFields' effect on cancer but not non-cancer cells because cancer cells need less field strength concentrations to trigger an effect.
“Since resting cancer cells are relatively depolarized compared to non-cancer cells, the same phenomenon likewise provides an explanation for TTFields’ effect on cancer but not non-cancer cells as the former needs less field strength concentrations to trigger an effect.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenAlterations in channel function might serve as a biomarker of AEF action.
“The effects of AEF on membrane function in cancers is insufficiently explained by the impact on voltage-gated calcium channels alone; however, alterations in channel function might serve as a biomarker of AEF action.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Interpretationnone givenTTFields' mechanisms of action is not yet fully elucidated.
“Despite its demonstrated clinical efficacy, TTFields’ mechanisms of action is not yet fully elucidated.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationCalcium influx and Cav2+ activation might serve as novel biomarkers of the efficacy of TTFields.
“Calcium influx and Cav2+ activation might also serve as novel biomarkers of the efficacy of TTFields [46].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [46] Neuhaus, E., Zirjacks, L., Ganser, K., Klumpp, L., Schüler, U., Zips, D., Eckert, F., and Huber, S.M. (2019). Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells. Cancers, 11. source
Not checked in the free run.
May combine two claims.
PremisecitationPTEN mutation leads to disruption of proper spindle assembly and chromosome segregation, resulting in mitotic catastrophe.
“PTEN mutation leads to disruption of proper spindle assembly and chromosome segregation, which results in mitotic catastrophe [93,94].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [93] He, 2016, PTEN regulates EG5 to control spindle architecture and chromosome congression during mitosis, Nat. Commun. source
Not checked in the free run.
- cites [94] Zhang, 2016, PTEN regulates PLK1 and controls chromosomal stability during cell division, Cell Cycle source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.
Interpretationown dataOur modeling indicates that using microfluidics to measure shear stress induced by TTFields and investigations into TTFields-induced alterations in transmembrane fenestration number, distribution, and size are pertinent to cancer research.
“Our modeling also indicates that using microfluidics to measure shear stress (τ) induced by TTFields and investigations into TTFields-induced alterations in transmembrane fenestration number, distribution, and size are pertinent to cancer research.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Interpretationnone givenIncreased cellular proliferation and density in cancer tissues could explain both the high field strength needed for the AEF effects described and why AEFs affect cancer but not non-cancer cells.
“The increased cellular proliferation and density in cancer tissues could explain both the high field strength needed for the AEF effects described herein as well as why AEFs affect cancer but not non-cancer cells.”
Quote in the paperNot a substantial claim- Rests on an assumption: Increased cellular proliferation and density occur in cancer tissues.
The authors state this as an assumption.
In the bioelectrorheological framework, the cell model consists of cytoplasm, membrane, and external medium simplified as homogeneous, with cytoplasm and medium considered non-viscous fluids and the membrane considered an elastic and viscous element.
“In the bioelectrorheological framework, the cell model consists of three parts—the cytoplasm, membrane, and external medium—which are all simplified to be homogeneous wherein the cytoplasm and medium are considered as non-viscous fluids while the membrane is considered an elastic and viscous element [53,57].”
The authors state this as an assumption.
The shear stress in the bioelectrorheological model is assumed to have developed due to Maxwell stress.
“The shear stress is assumed to have developed due to Maxwell stress [53].”
The authors state this as an assumption.
To analyze extensile stress, the model of the cell is simplified to an elastic shell assumed to be homogeneous with constant volume and slightly compressible area and thickness.
“To analyze extensile stress, the model of the cell is simplified to an elastic shell assumed to be homogeneous with constant volume and slightly compressible area and thickness [40].”
The authors state this as an assumption.
Internal and external media in the extensile stress model are assumed to be isotropic, noncompressible, non-viscous liquids.
“Internal and external media are also assumed to be isotropic, noncompressible, non-viscous liquids.”
The authors state this as an assumption.
Changes in shell thickness, area, and volume (which is assumed to be zero) are used to calculate the magnitude of extensile stress caused by oscillating electric fields.
“Changes in shell thickness, area, and volume (which is assumed to be zero) are used to calculate the magnitude of extensile stress caused by oscillating electric fields [40].”
The authors state this as an assumption.
TTFields act on voltage-gated Cav2+ channels.
“However, if we assume TTFields act on voltage-gated Cav2+ channels, the diameter of the channels is on the order of a few nanometers and therefore is too small to associate them with the pores shown by Chang et al. to be created or enlarged by TTFields”
The paper relies on this without support.
Most computational modeling studies are based upon single cells in isolation.
“The resolution of the observed versus theoretical discrepancies may stem from the fact that most computational modeling studies are based upon single cells in isolation.”
The paper relies on this without support.
Mitotic spindles are not the only biological structures that possess intrinsic dipole moments.
“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.”
The paper relies on this without support.
DNA possesses 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].”
The paper relies on this without support.
Increased cellular proliferation and density occur in cancer tissues.
“The increased cellular proliferation and density in cancer tissues could explain both the high field strength needed for the AEF effects described herein as well as why AEFs affect cancer but not non-cancer cells.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Electric field treatment of glioblastoma has been approved by the US FDA, indicating that it is feasible to introduce electric fields to cancer treatment.
“For example, electric field treatment of glioblastoma has been approved by the US FDA, indicating that it is feasible to introduce electric fields to cancer treatment.181”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [181]
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- Authors
- Aguilar, A. A., Ho, M. C., Chang, E., Carlson, K. W., Natarajan, A., Marciano, T., Bomzon, Z., & Patel, C. B.
- Affiliations
- Stanford Medicine (US)
- Beth Israel Deaconess Medical Center (US)
- Novocure, Ltd., 31905 Haifa, Israel
- Corresponding author
- Patel, Chirag B.
- ORCID
- Venue
- Cancers
- Publisher
- MDPI AG
- Published
- 2021-05-10
- Volume
- 13
- Issue
- 9
- Pages
- 2283
- ISSN
- 2072-6694 (ISSN-L)
- PMC
- PMC8126200
- OpenAlex
- W3162801462
- Semantic Scholar
- 041e23c8d7f480d5a585523f34e670da3729d7e1
- Cited by
- 76
- References
- 100
- Citations by year
- 2026: 11 · 2025: 16 · 2024: 11 · 2023: 19 · 2022: 13 · 2021: 6
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancers (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Novocure
- School of Medicine, Stanford University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Inactivation Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- tumor treating fields, AC electric field, cell membrane permeabilization, electroporation, voltage-gated ion channels, mitotic spindle disruption, glioblastoma, mesothelioma, electric field inhomogeneity, tumor cell membrane, mechanism of action
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
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