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Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells
Open accessAbstract
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.
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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.
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“Comparable results demonstrating enhanced efficacy achieved by increasing treatment duration were also obtained for the AsPC-1 cell line (data not shown).”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Efficacy can be Enhanced by Extending Treatment Duration
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In the paper
“There were no observed differences in total tubulin levels between control and TTFields treated cells (data not shown).”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Interfere With Mitotic Spindle Structure
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In the paper
“Multinuclear progeny were also formed in U-87 MG following 72 hours exposure to TTFields.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Treatment Results in the Formation of Multiple Nuclei within Cancer Cells
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In the paper
“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).”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Exposure Cause Both Mitotic Cell Death and Death in Interphase
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In the paper
“Of note, we also conducted Giemsa staining analysis, the results of which excluded the possibility of partial chromosomal loss (data not shown).”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Treatment Results in a Divergence from Normal Chromosomes Counts
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In the paper
“A significant positive Spearman rank correlation was found between treated cell doubling time and both cell count (r = 0.7939; p = 0.008) and clonogenic survival (r = 0.7212; p = 0.023) following TTFields exposure (Fig. 3C).”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > Variations in Response to TTFields are Independent of Model Chromosome Number and can be Explained by Differences in Cell Doubling Time
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In the paper
“cells treated with TTFields 6 hours after re-plating, (a time point at which rapid microtubule turnover rates exist), contained increased levels of depolymerized tubulin compared to untreated cells (p = 0.011).”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Interfere With Mitotic Spindle Structure
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In the paper
“SKY analysis and chromosome spreads (metaphase spreads) were performed and these revealed that cells treated with TTFields show a large variation in chromosomal counts (Fig. 2E–H).”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Treatment Results in a Divergence from Normal Chromosomes Counts
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“caspase dependent apoptosis of daughter cells”
- Also stated in: § TTFields Exposure Induces Caspase-Mediated Cell Death · boosted
“apoptosis was completely abrogated in the presence of Z-VAD-FMK confirming that TTFields induced cell death was caspase dependent”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § TTFields Exposure Induces Caspase-Mediated Cell Death · boosted
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In the paper
“There is a dramatic increase in the number of hypodiploid cells, characterized by complete chromosomal loss and this may provide a potential explanation to the observed increase in the percentage of resultant micronuclear structures.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Treatment Results in a Divergence from Normal Chromosomes Counts
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- It may state two separate claims as one. 18
- The quote only partly states this claim. 2
- Probably not a substantial claim. 16
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In the paper
“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.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Exposure Cause Both Mitotic Cell Death and Death in Interphase
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- Also stated in: § TTFields Exposure Cause Both Mitotic Cell Death and Death in Interphase · hedged
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In the paper
“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).”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Efficacy can be Enhanced by Extending Treatment Duration
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In the paper
“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.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Treatment Results in the Formation of Multiple Nuclei within Cancer Cells
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In the paper
“Extension of treatment duration proved to enhance treatment efficacy as gradual decreases in both cell viability and clonogenic survival were observed as treatment continued.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Discussion
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In the paper
“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).”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Exposure Induces Caspase-Mediated Cell Death
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In the paper
“Therefore, although long-term effects of TTFields are maintained after a treatment break, extending the duration of TTFields application resulted in improved treatment outcomes.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Efficacy can be Enhanced by Extending Treatment Duration
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Interfere With Mitotic Spindle Structure
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: Electric fields exert directional forces on polar intracellular elements such as organelles and macromolecules.
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In the paper
“Taken together, these results suggest that TTFields treatment results in nuclear aberrations including multinucleation, which is a sign of mitotic catastrophe21.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Treatment Results in the Formation of Multiple Nuclei within Cancer Cells
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In the paper
“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.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > Variations in Response to TTFields are Independent of Model Chromosome Number and can be Explained by Differences in Cell Doubling Time
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In the paper
“Silk et al. have recently suggested that levels of aneuploidy elevated beyond a certain threshold, suppress tumors by causing cell death46.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Discussion
What the sources say
- Not checked yetcites Silk et al.
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In the paper
“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.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Methods > Cell culture and drugs
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In the paper
“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.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Discussion
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In the paper
“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.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Discussion
What the sources say
- Not checked yetcites [17] Gascoigne, K. E. & Taylor, S. S. How do anti-mitotic drugs kill cancer cells? J. Cell Sci. 122, 2579–2585 (2009). source
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In the paper
“Alternatively mitotically arrested cells can escape mitosis to enter G1 phase as polyploid cells, in a process known as mitotic slippage262930.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Abstract
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
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In the paper
“Atypical mitotic figures were determined in a blinded fashion based on intact or chromosome configurations during metaphase and anaphase.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Methods > Classification of mitotic disturbances and mitotic index in tumors
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In the paper
“The Sham heat electrodes produced equal temperature changes to those produced by the field electrodes by means of a heating resistor incorporated within them.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Methods > TTFields application in vivo
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In the paper
“Control rats were treated by means of sham electrodes which were geometrically matched to the TTFields group.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Methods > TTFields application in vivo
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In the paper
“Missegregation of chromosomes results in aneuploidy, which can lead to genomic instability and subsequent cell death or senescence in a process termed mitotic catastrophe21.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Abstract
What the sources say
- Not checked yetcites [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
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While prolonged mitotic arrest can occur following TTFields exposure, cell death during the subsequent interphase is more prevalent.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Discussion
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In the paper
“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.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Abstract
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
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In the paper
“In addition, cell death can also occur following cell division21.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Abstract
What the sources say
- Not checked yetcites [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
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In the paper
“Anti-microtubule agents are thought to delay mitotic progression by activating the SAC, thereby inducing mitotic arrest and cell death directly from mitosis24.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Abstract
What the sources say
- Not checked yetcites [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
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In the paper
“All available slides were reviewed by independent pathologist (Ori Brenner, DACVP), and average mitotic rate was blindly evaluated.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Methods > Classification of mitotic disturbances and mitotic index in tumors
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Results > TTFields Exposure Cause Both Mitotic Cell Death and Death in Interphase
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Discussion
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In the paper
“The mitotic spindle governs the requisite capturing, alignment, and segregation of chromosomes to two daughter cells1920.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Abstract
What the sources say
- Not checked yetcites [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 yetcites [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
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In the paper
“Senescence, cell death via apoptosis, and continued cell cycling are all possible outcomes of mitotic slippage29.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Abstract
What the sources say
- Not checked yetcites [29] Yamada, H. Y. & Gorbsky, G. J. Spindle checkpoint function and cellular sensitivity to antimitotic drugs. Mol. Cancer Ther. 5, 2963–2969 (2006). source
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“These observations are in line with growing body of evidence suggesting both inter and intra–line variation in response to anti-mitotic drugs176364.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Discussion
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“At least 120 cells in metaphase or anaphase were analyzed in each group.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Methods > Classification of mitotic disturbances and mitotic index in tumors
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our results provide the first evidence supporting the direct effect of TTFields on microtubules, and specific effects on spindle assembly in replicating cells.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells > Discussion
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
- The authors state this as an assumption: The application of TTFields resembles a state in which constant drug concentration is delivered to the tumor.
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.”
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?
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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].”
From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [8]
In the citing paper
“TTFields were shown to induce an anti-mitotic effect by exerting bi-directional forces on highly polar intracellular elements, such as tubulin and septin molecules, eliciting abnormal microtubule polymerization during spindle formation as well as aberrant cleavage furrow formation.”
From Tumor Treating Fields (TTFields) Hinder Cancer Cell Motility through Regulation of Microtubule and Actin Dynamics (2020) · cites this paper as [6]
In the citing paper
“Tumor treating fields (TTFields) are low-intensity electric fields alternating at an intermediate frequency (200kHz), which have been demonstrated to block cell division and interfere with organelle assembly.”
From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [10]
In the citing paper
“This effect also results in abnormal chromosomal segregation and reduced clonogenic potential of the cell’s progeny.10”
From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [10]
In the citing paper
“TTFields will target proteins with large dipole moments (ie, septins and the spindle microtubules, components essential in the metaphase and anaphase stages of the mitotic cycle for separation and equal distribution of chromosomes).9,10”
From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [10]
In the citing paper
“Further studies demonstrated that the growth inhibitory effect is largely mediated by interference on the mitotic spindle apparatus.”
From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [10]
In the citing paper
“TTFields application leads to abnormal mitosis, aneuploidy, and increased cell granularity, which are often associated with enhancement of autophagy.”
From AMPK-dependent autophagy upregulation serves as a survival mechanism in response to Tumor Treating Fields (TTFields) (2018) · 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
MinorThe 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.
“while exposed to 150 Hz TTFields.”
“TTFields are low-intensity (1–3 V/cm) intermediate-frequency (100–300 kHz), alternating electric fields.”
The claimed field intensity for all studies differs from the rat experiment
MinorThe paper says 175 V/m was used for all studies, but reports applying 200 V/m in the rat experiment.
“Field intensity of 175 V/m was used for all studies”
“TTFields (200 V/m) were applied for 7 days using the optimal frequency of 200 kHz.”
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Metadata
- 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
- Venue
- Scientific Reports
- Published
- 2015-12-11
- Volume
- 5
- Issue
- 1
- Pages
- 18046-18046
- ISSN
- 2045-2322 (ISSN-L)
- 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
- gold
- doi.org
- 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
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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.
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