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Cited by 327Microtubule and mitosis dynamicsElectromagnetic Fields and Biological EffectsMicrobial Inactivation Methods

Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells

Open access
Giladi, Moshe, Schneiderman, Rosa S, Voloshin, Tali, Porat, Yaara, Munster, Mijal, Blat, Roni, Sherbo, Shay, Bomzon, Zeev +8 more·2015·Scientific Reports
DOI 10.1038/srep18046PMC PMC4676010
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Abstract

Tumor Treating Fields (TTFields) are low intensity, intermediate frequency, alternating electric fields. TTFields are a unique anti-mitotic treatment modality delivered in a continuous, noninvasive manner to the region of a tumor. It was previously postulated that by exerting directional forces on highly polar intracellular elements during mitosis, TTFields could disrupt the normal assembly of spindle microtubules. However there is limited evidence directly linking TTFields to an effect on microtubules. Here we report that TTFields decrease the ratio between polymerized and total tubulin and prevent proper mitotic spindle assembly. The aberrant mitotic events induced by TTFields lead to abnormal chromosome segregation, cellular multinucleation and caspase dependent apoptosis of daughter cells. The effect of TTFields on cell viability and clonogenic survival substantially depends upon the cell division rate. We show that by extending the duration of exposure to TTFields, slowly dividing cells can be affected to a similar extent as rapidly dividing cells.

AI snapshot

Written from the paper’s full text.

TL;DR

TTFields (low-intensity, intermediate-frequency alternating electric fields) disrupt mitotic spindle microtubules, reduce polymerized tubulin, and cause chromosome missegregation, multinucleation, and caspase-dependent apoptosis in cancer cells. Treatment efficacy depends strongly on cell division rate, and extending exposure improves effects in slowly dividing cells.

Key findings

  • TTFields decreased the polymerized-to-total tubulin ratio in A2780 ovarian carcinoma cells after 48 h at 200 kHz (12.8% decrease, p = 0.021), and increased depolymerized tubulin under rapid-turnover conditions after trypsinization/re-plating (p = 0.011); no significant change was seen at the slower-turnover 30-h time point.
  • TTFields caused abnormal mitotic spindle geometry and multinucleation: in U-87 MG cells, abnormal cells with multiple nuclei/micronuclear structures increased from 2% to 8% after 72 h (P = 0.002), and in MSTO-211H mesothelioma cells from 1% to 18% after 150 kHz treatment (P < 0.0001).
  • In Fischer rats with intracranial F-98 glioma, 7 days of 200 kHz TTFields at 200 V/m reduced tumor volume fold increase by 41% (p = 0.05; n = 14 treated vs n = 13 control) and significantly reduced normal metaphase and anaphase figures (p < 0.001 for both).
  • Across ten solid-tumor cell lines, all showed reduced cell count and clonogenic survival after 72 h TTFields, but response did not correlate with model chromosome number; it did correlate with doubling time for cell count (Spearman r = 0.7939; p = 0.008) and clonogenic survival (r = 0.7212; p = 0.023). Longer exposure improved efficacy in A2780 (doubling time 18.7 h), U-87 MG (39 h), and AsPC-1 (54 h) cells.

Methods

  • In vitro: multiple human cancer cell lines (e.g., A2780, A549, MDA-MB-231, U-87 MG, HeLa, MSTO-211H, AsPC-1) were treated with TTFields using the inovitro system at 175 V/m and cell-type-specific optimal frequencies; in vivo: F-98 glioma cells were implanted intracranially in Fischer rats and treated with 200 kHz TTFields at 200 V/m for 7 days, with tumor volume assessed by MRI and mitotic figures by H&E.
  • Assays included confocal fluorescence microscopy of mitotic spindles, tubulin polymerization assays with Western blotting for α-tubulin, time-lapse video microscopy of HeLa cells expressing Tubulin-GFP, flow cytometry for cell cycle/Annexin V/PI/caspase activity, SKY and chromosome spreads, cell counts, clonogenic survival, and β-galactosidase senescence assays.
  • Statistics used one-way ANOVA with Tukey’s test unless otherwise stated, and Spearman rank correlation for doubling time versus cell count/clonogenic survival.

Limitations

  • Stated: whether TTFields directly interfere with tubulin subunit addition or destroy existing microtubules remains undetermined; higher-resolution studies are needed. The initial triggers of caspase-dependent apoptosis are not fully understood, and it remains unclear whether post-mitotic death is solely due to aneuploidy or also delayed damage from mitosis.
  • Stated: the authors lack a clear explanation for divergent cell fates after TTFields exposure, and future randomized clinical trials are needed to confirm whether extended treatment duration improves clinical outcomes.
  • Evident: most mechanistic data are from in vitro cancer cell lines, with only one rat glioma model; several results are reported as “data not shown,” and p53 status, SAC status, and apoptotic signaling differences are proposed but not resolved in this study.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/srep18046

Cites

69 of 69 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 30 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Comparable results demonstrating enhanced efficacy achieved by increasing treatment duration were also obtained for AsPC-1 cell line.

    “Comparable results demonstrating enhanced efficacy achieved by increasing treatment duration were also obtained for the AsPC-1 cell line (data not shown).”
    Quote in the paperNot a substantial claim
  • Findingown data

    There were no observed differences in total tubulin levels between control and TTFields treated cells.

    “There were no observed differences in total tubulin levels between control and TTFields treated cells (data not shown).”
    Quote in the paperSubstantial claim
  • Findingown data

    Multinuclear progeny were formed in U-87 MG following 72 hours exposure to TTFields.

    “Multinuclear progeny were also formed in U-87 MG following 72 hours exposure to TTFields.”
    Quote in the paperSubstantial claim
  • Findingown data

    One or both daughter cells underwent cell death (67% of mitotic cells) within 21.5 ± 19.4 hours following mitosis.

    “Follow-up observations for the resulting progeny revealed that one or both daughter cells underwent cell death (67% of mitotic cells) within 21.5 ± 19.4 hours following mitosis (Supplementary Movie S2).”
    Quote in the paperSubstantial claim
  • Findingown data

    Giemsa staining analysis excluded the possibility of partial chromosomal loss.

    “Of note, we also conducted Giemsa staining analysis, the results of which excluded the possibility of partial chromosomal loss (data not shown).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 18
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Findingown data

    TTFields exposure causes both mitotic cell death and death in interphase.

    “TTFields Exposure Cause Both Mitotic Cell Death and Death in Interphase”
    • Also stated in: § TTFields Exposure Cause Both Mitotic Cell Death and Death in Interphase · hedged
      “Overall, our data suggest that TTFields treated cells exhibit small delays in mitosis following which some cells die in mitosis while others eventually divide and continue to the next interphase.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    A longer period of exposure to TTFields resulted in a significant decrease in both cell count and clonogenic survival in U-87 MG cells (doubling time 39 hours).

    “A longer period of exposure to TTFields resulted in a significant decrease in both cell count and clonogenic survival in U-87 MG cells (Fig. 4C,D).”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Time-lapse video microscopy revealed disruption of spindle structure followed by formation of binucleate or polynucleate progeny in HeLa cells expressing Tubulin-GFP exposed to 150 Hz TTFields.

    “Time-lapse video microscopy was utilized to directly visualize spindle structure and nuclei in the daughter cells of HeLa cervix adenocarcinoma cells expressing Tubulin-GFP (green fluorescent protein) fusion protein while exposed to 150 Hz TTFields.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Extension of TTFields treatment duration enhances treatment efficacy, as gradual decreases in both cell viability and clonogenic survival were observed as treatment continued.

    “Extension of treatment duration proved to enhance treatment efficacy as gradual decreases in both cell viability and clonogenic survival were observed as treatment continued.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    While average cell count of A2780 cells treated with TTFields for 48 hours was 52 percent, in presence of Z-VAD-FMK cell count rose to 79 percent.

    “While the average cell count of A2780 cells treated with TTFields for 48 hours was 52 percent, in the presence of Z-VAD- FMK cell count rose to 79 percent (Fig. 6E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Although long-term effects of TTFields are maintained after a treatment break, extending the duration of TTFields application resulted in improved treatment outcomes.

    “Therefore, although long-term effects of TTFields are maintained after a treatment break, extending the duration of TTFields application resulted in improved treatment outcomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Under rapid turnover conditions, TTFields decrease the ratio of polymerized to total tubulin, providing a putative explanation for disruption of the mitotic spindle assembly apparatus.

    “Taken together, these results demonstrate that under rapid turnover conditions, TTFields decrease the ratio of polymerized to total tubulin, thus providing a putative explanation for the disruption of the mitotic spindle assembly apparatus.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Electric fields exert directional forces on polar intracellular elements such as organelles and macromolecules.

  • May combine two claims.

    Interpretationown data

    TTFields treatment results in nuclear aberrations including multinucleation, which is a sign of mitotic catastrophe.

    “Taken together, these results suggest that TTFields treatment results in nuclear aberrations including multinucleation, which is a sign of mitotic catastrophe21.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Within any given treatment period, rapidly dividing cells are more likely to be affected by TTFields while non dividing cells remain intact.

    “Together, these results demonstrate that within any given treatment period, rapidly dividing cells are more likely to be affected by TTFields while non dividing cells remain intact.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Levels of aneuploidy elevated beyond a certain threshold suppress tumors by causing cell death.

    “Silk et al. have recently suggested that levels of aneuploidy elevated beyond a certain threshold, suppress tumors by causing cell death46.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Silk et al.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Differences within the range of 2-6% between the average resistivity and current density of the different media were measured and considered to be negligible.

    “Differences within the range of 2-6% between the average resistivity and current density of the different media were measured and considered to be negligible.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Cells entering mitosis are those most likely to respond to TTFields because the mechanism of action involves disruption of spindle microtubules leading to mitotic catastrophe.

    “As the mechanism of action of TTFields involves disruption of spindle microtubules, consequently leading to mitotic catastrophe, cells entering mitosis are those most likely to respond to TTFields.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Effective doses of systemic drugs vary greatly and depend on pharmacokinetic and pharmacodynamic factors such as plasma concentration and elimination half-life.

    “It should be acknowledged, however, that the effective doses of systemic drugs vary greatly and are dependent on pharmacokinetic and pharmacodynamic factors such as plasma concentration and elimination half life17.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Gascoigne, K. E. & Taylor, S. S. How do anti-mitotic drugs kill cancer cells? J. Cell Sci. 122, 2579–2585 (2009). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mitotically arrested cells can escape mitosis to enter G1 phase as polyploid cells, in a process known as mitotic slippage.

    “Alternatively mitotically arrested cells can escape mitosis to enter G1 phase as polyploid cells, in a process known as mitotic slippage262930.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [26] Rieder, C. L. & Maiato, H. Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. Dev. Cell 7, 637–651 (2004). source

      Not checked in the free run.

    • cites [29] Yamada, H. Y. & Gorbsky, G. J. Spindle checkpoint function and cellular sensitivity to antimitotic drugs. Mol. Cancer Ther. 5, 2963–2969 (2006). source

      Not checked in the free run.

    • cites [30] Elhajouji, A., Cunha, M. & Kirsch-Volders, M. Spindle poisons can induce polyploidy by mitotic slippage and micronucleate mononucleates in the cytokinesis-block assay. Mutagenesis 13, 193–198 (1998). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Atypical mitotic figures were determined in a blinded fashion based on intact or chromosome configurations during metaphase and anaphase.

    “Atypical mitotic figures were determined in a blinded fashion based on intact or chromosome configurations during metaphase and anaphase.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The sham heat electrodes produced equal temperature changes to those produced by the field electrodes.

    “The Sham heat electrodes produced equal temperature changes to those produced by the field electrodes by means of a heating resistor incorporated within them.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Control rats were treated with sham electrodes geometrically matched to the TTFields group.

    “Control rats were treated by means of sham electrodes which were geometrically matched to the TTFields group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Missegregation of chromosomes results in aneuploidy, which can lead to genomic instability and subsequent cell death or senescence in a process termed mitotic catastrophe.

    “Missegregation of chromosomes results in aneuploidy, which can lead to genomic instability and subsequent cell death or senescence in a process termed mitotic catastrophe21.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Vitale, I., Galluzzi, L., Castedo, M. & Kroemer, G. Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat. Rev. Mol. Cell Biol. 12, 385–392 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    While prolonged mitotic arrest can occur following TTFields exposure, cell death during subsequent interphase is more prevalent.

    “While prolonged mitotic arrest can occur following TTFields exposure, cell death during the subsequent interphase is more prevalent.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The SAC is responsible for delaying the irreversible transition from metaphase to anaphase in order to avoid erroneous segregation of sister chromatids.

    “The SAC, also known as the mitotic checkpoint, is responsible for delaying the irreversible transition from metaphase to anaphase in order to avoid erroneous segregation of sister chromatids222324.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] Musacchio, A. & Hardwick, K. G. The spindle checkpoint: structural insights into dynamic signalling. Nat. Rev. Mol. Cell Biol. 3, 731–741 (2002). source

      Not checked in the free run.

    • cites [23] Musacchio, A. & Salmon, E. D. The spindle-assembly checkpoint in space and time. Nat. Rev. Mol. Cell Biol. 8, 379–393 (2007). source

      Not checked in the free run.

    • cites [24] Weaver, B. A. & Cleveland, D. W. Decoding the links between mitosis, cancer and chemotherapy: The mitotic checkpoint, adaptation and cell death. Cancer Cell 8, 7–12 (2005). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cell death can also occur following cell division.

    “In addition, cell death can also occur following cell division21.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Vitale, I., Galluzzi, L., Castedo, M. & Kroemer, G. Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat. Rev. Mol. Cell Biol. 12, 385–392 (2011). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Anti-microtubule agents are thought to delay mitotic progression by activating the SAC, thereby inducing mitotic arrest and cell death directly from mitosis.

    “Anti-microtubule agents are thought to delay mitotic progression by activating the SAC, thereby inducing mitotic arrest and cell death directly from mitosis24.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Weaver, B. A. & Cleveland, D. W. Decoding the links between mitosis, cancer and chemotherapy: The mitotic checkpoint, adaptation and cell death. Cancer Cell 8, 7–12 (2005). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    All available slides were reviewed by an independent pathologist, and average mitotic rate was blindly evaluated.

    “All available slides were reviewed by independent pathologist (Ori Brenner, DACVP), and average mitotic rate was blindly evaluated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    TTFields treated cells exhibit small delays in mitosis following which some cells die in mitosis while others eventually divide and continue to the next interphase.

    “Overall, our data suggest that TTFields treated cells exhibit small delays in mitosis following which some cells die in mitosis while others eventually divide and continue to the next interphase.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    TTFields frequencies utilized in this series are the specific frequencies that led to highest reduction in cell counts, most likely by virtue of their effect on mitotic spindle.

    “TTFields frequencies utilized in this series of investigation are the specific frequencies that have led to the highest reduction in cell counts, most likely by virtue of their effect on the mitotic spindle.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The mitotic spindle governs the requisite capturing, alignment, and segregation of chromosomes to two daughter cells.

    “The mitotic spindle governs the requisite capturing, alignment, and segregation of chromosomes to two daughter cells1920.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Kline-Smith, S. L. & Walczak, C. E. Mitotic spindle assembly and chromosome segregation: refocusing on microtubule dynamics. Mol. Cell 15, 317–327(2004). source

      Not checked in the free run.

    • cites [20] Gordon, M. B., Howard, L. & Compton, D. A. Chromosome movement in mitosis requires microtubule anchorage at spindle poles. J. Cell Biol. 152, 425–434 (2001). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Senescence, cell death via apoptosis, and continued cell cycling are all possible outcomes of mitotic slippage.

    “Senescence, cell death via apoptosis, and continued cell cycling are all possible outcomes of mitotic slippage29.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Yamada, H. Y. & Gorbsky, G. J. Spindle checkpoint function and cellular sensitivity to antimitotic drugs. Mol. Cancer Ther. 5, 2963–2969 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There is inter- and intra-line variation in response to anti-mitotic drugs.

    “These observations are in line with growing body of evidence suggesting both inter and intra–line variation in response to anti-mitotic drugs176364.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Gascoigne, K. E. & Taylor, S. S. How do anti-mitotic drugs kill cancer cells? J. Cell Sci. 122, 2579–2585 (2009). source

      Not checked in the free run.

    • cites [63] Orth, J. D. et al. Quantitative live imaging of cancer and normal cells treated with Kinesin-5 inhibitors indicates significant differences in phenotypic responses and cell fate. Mol. Cancer Ther. 7, 3480–3489 (2008). source

      Not checked in the free run.

    • cites [64] Shi, J., Orth, J. D. & Mitchison, T. Cell type variation in responses to antimitotic drugs that target microtubules and kinesin-5. Cancer Res. 68, 3269–3276 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    At least 120 cells in metaphase or anaphase were analyzed in each group.

    “At least 120 cells in metaphase or anaphase were analyzed in each group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Results provide first evidence supporting direct effect of TTFields on microtubules, and specific effects on spindle assembly in replicating cells.

    “Our results provide the first evidence supporting the direct effect of TTFields on microtubules, and specific effects on spindle assembly in replicating cells.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Data obtained from cell culture studies might advance understanding of in vivo response to TTFields, ultimately enhancing clinical trial designs to improve patient outcomes.

    “Therefore, it is likely that data obtained from cell culture studies might indeed advance our understanding of in vivo response to TTFields, ultimately enhancing clinical trial designs to improve patient outcomes.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The application of TTFields resembles a state in which constant drug concentration is delivered to the tumor.
31 of 31

  • The authors state this as an assumption.

    Electric fields exert directional forces on polar intracellular elements such as organelles and macromolecules.

    “A commonality among these hypotheses is the assumption that electric fields exert directional forces on polar intracellular elements such as organelles and macromolecules.”

  • The authors state this as an assumption.

    The progeny of cells that succeeded in completing previous mitosis under TTFields treatment were further damaged on consecutive mitotic events as treatment duration was extended.

    “It is reasonable to assume that the progeny of cells which succeeded in completing previous mitosis under TTFields treatment were further damaged on the consecutive mitotic events as the treatment duration was extended.”

  • The authors state this as an assumption.

    The application of TTFields resembles a state in which constant drug concentration is delivered to the tumor.

    “In this context, the application of TTFields presumably resembles a state in which constant drug concentration is delivered to the tumor.”
3 of 3

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?

  • TTFields-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].”

    From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [8]

  • 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].”

    From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [8]

  • The 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].”

    From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [8]

  • The 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.”

    From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [8]

  • Mitotic 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.”

    From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [8]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • HeLa treatment frequency falls outside the stated TTFields range

    Minor

    The HeLa time-lapse experiment says it used 150 Hz TTFields, whereas the paper defines TTFields as operating at 100-300 kHz. The stated experimental frequency is outside that range.

  • The claimed field intensity for all studies differs from the rat experiment

    Minor

    The paper says 175 V/m was used for all studies, but reports applying 200 V/m in the rat experiment.

2 of 2

Cites

Flagged first, then by citations

1 of the 70 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Elson, E. Biologic effects of radiofrequency and microwave fields: in vivo and in vitro experimental results in The biomedical engineering handbook (ed. Bronzino, J. D. ) 1417–1423 (CRC Press, 1995).

Cited by

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Authors
Giladi, M., Schneiderman, R. S., Voloshin, T., Porat, Y., Munster, M., Blat, R., Sherbo, S., Bomzon, Z., Urman, N., Itzhaki, A., Cahal, S., Shteingauz, A., Chaudhry, A., Kirson, E. D., Weinberg, U., & Palti, Y.
Corresponding author
Giladi, Moshe
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2015-12-11
Volume
5
Issue
1
Pages
18046-18046
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep18046
PMC
PMC4676010
OpenAlex
W2196065821
Cited by
327
References
70
Citations by year
2026: 31 · 2025: 28 · 2024: 32 · 2023: 40 · 2022: 47 · 2021: 34 · 2020: 34 · 2019: 27 · 2018: 28 · 2017: 15 · 2016: 11
FWCI
9.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Inactivation Methods
Keywords
tumor treating fields, AC electric field, mitotic spindle disruption, microtubule assembly, tubulin, chromosome segregation, mitotic catastrophe, multinucleation, caspase-dependent apoptosis, clonogenic survival, cell division rate, tumor cell viability
MeSH terms
Animals, Cell Survival, Electricity, Humans, Microtubules, Mitosis, Spindle Apparatus, Neoplasms, Rats, Inbred F344, Tubulin, Apoptosis, Chromosome Segregation, Cell Line, Tumor, Rats, MCF-7 Cells

About these checks

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.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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