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Cited by 137Glioma Diagnosis and TreatmentMicrobial Inactivation MethodsElectromagnetic Fields and Biological Effects

Tumor treating fields increases membrane permeability in glioblastoma cells

Open access
Chang, Edwin, Patel, Chirag B., Pohling, Christoph, Young, Caroline, Song, Jonathan, Flores, Thomas Anthony, Zeng, Yitian, Joubert, Lydia-Marie +4 more·2018·Cell Death Discovery
DOI 10.1038/s41420-018-0130-xPMC PMC6281619
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Abstract

Glioblastoma is the most common yet most lethal of primary brain cancers with a one-year post-diagnosis survival rate of 65% and a five-year survival rate of barely 5%. Recently the U.S. Food and Drug Administration approved a novel fourth approach (in addition to surgery, radiation therapy, and chemotherapy) to treating glioblastoma; namely, tumor treating fields (TTFields). TTFields involves the delivery of alternating electric fields to the tumor but its mechanisms of action are not fully understood. Current theories involve TTFields disrupting mitosis due to interference with proper mitotic spindle assembly. We show that TTFields also alters cellular membrane structure thus rendering it more permeant to chemotherapeutics. Increased membrane permeability through the imposition of TTFields was shown by several approaches. For example, increased permeability was indicated through increased bioluminescence with TTFields exposure or with the increased binding and ingress of membrane-associating reagents such as Dextran-FITC or ethidium D or with the demonstration by scanning electron microscopy of augmented number and sizes of holes on the cellular membrane. Further investigations showed that increases in bioluminescence and membrane hole production with TTFields exposure disappeared by 24 h after cessation of alternating electric fields thus demonstrating that this phenomenom is reversible. Preliminary investigations showed that TTFields did not induce membrane holes in normal human fibroblasts thus suggesting that the phenomenom was specific to cancer cells. With TTFields, we present evidence showing augmented membrane accessibility by compounds such as 5-aminolevulinic acid, a reagent used intraoperatively to delineate tumor from normal tissue in glioblastoma patients. In addition, this mechanism helps to explain previous reports of additive and synergistic effects between TTFields and other chemotherapies. These findings have implications for the design of combination therapies in glioblastoma and other cancers and may significantly alter standard of care strategies for these diseases.

AI snapshot

Written from the paper’s full text.

TL;DR

Tumor treating fields (TTFields) increase plasma membrane permeability in glioblastoma cells, allowing greater uptake of small molecules and chemotherapeutics. This effect is reversible after TTFields cessation and appears specific to cancer cells in preliminary comparisons with normal human fibroblasts.

Key findings

  • TTFields (4 V/cm, 200 kHz, 0.5–24 h) significantly increased bioluminescence in luciferase-expressing U87-MG/eGFP-fLuc cells as early as 30 min and through 24 h (p < 0.0001, two-way ANOVA), without significantly increasing eGFP fluorescence.
  • Uptake of Dextran-FITC was significantly increased for 4 kDa (p < 0.0001) and 20 kDa (p < 0.01) dextrans, but not for 50 kDa dextran (p = 0.26, not significant).
  • SEM showed TTFields-exposed U87-MG cells had more holes ≥51.8 nm² (53.5 ± 19.1 vs. 23.9 ± 11.0, p = 0.0002) and larger average hole size (240.6 ± 91.7 nm² vs. 129.8 ± 31.9 nm², p = 0.0005) than unexposed cells; normal human PCS-201 fibroblasts showed no significant change.
  • TTFields increased 5-ALA uptake/PpIX fluorescence in U87-MG cells at 6 h (p = 0.047) and 24 h (p = 0.011), and in U87-MG/PCS-201 co-cultures (p < 0.001); the tumor-to-fibroblast PpIX ratio increased at 24 h (p = 0.043). Effects on bioluminescence, PpIX fluorescence, Dextran-FITC fluorescence, and SEM holes were attenuated after 24 h off TTFields.

Methods

  • Cell lines: patient-derived GBM2 and GBM39, commercial U87-MG, murine KR158B astrocytoma, and normal human PCS-201 fibroblasts; some lines were engineered to express firefly, Renilla, or GFP-fusion luciferases.
  • TTFields were applied in vitro using the inovitro system at 200 kHz (1–4 V/cm) for 0.5–72 h, with reversibility experiments after 24 h off TTFields; readouts included bioluminescence imaging, fluorescence imaging for Ethidium D, Dextran-FITC, and 5-ALA/PpIX, and scanning electron microscopy.
  • Statistical analysis used PRISM 7.0; normally distributed data were analyzed by Student’s t-test or ANOVA, non-normal data by non-parametric tests such as Mann–Whitney U, with alpha = 0.05 and post-hoc corrections for multiple comparisons.

Limitations

  • The paper states that results could not be confirmed in an animal model of glioblastoma because a practical device delivering TTFields to rodent brain does not yet exist.
  • The paper states that work focused on glioblastoma cells using 200 kHz TTFields because FDA approval exists only for glioblastoma and only at this frequency.
  • Evident from the text: experiments used unsynchronized cells, and the normal-fibroblast comparison is described as preliminary; the study is in vitro and does not establish clinical efficacy or blood-brain barrier effects.

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

Integrity signals

Registry

Crossref · 10.1038/s41420-018-0130-x

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 11 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    SEM showed a significantly increased number of holes greater than 51.8 nm2 within the ROI of TTFields-exposed U87-MG/eGFP-fLuc cells (53.5 ± 19.1) compared to TTFields-unexposed cells (23.9 ± 11.0), p = 0.0002.

    “There was a significantly increased number of holes greater than 51.8 nm2 in size (equivalent to 9 pixels2 on 60,000× magnification) within the ROI of TTFields-exposed cells (53.5 ± 19.1) compared to the TTFields-unexposed cells (23.9 ± 11.0), (p = 0.0002, univariate Mann–Whitney test).”
    Quote in the paperSubstantial claim
  • Findingown data

    Increased membrane permeability caused by TTFields exposure is demonstrated with Dextran-FITC and Ethidium D.

    “Increased membrane permeability caused by TTFields exposure is also demonstrated with other membrane-penetrating reagents such as Dextran-FITC and Ethidium D.”
    Quote in the paperSubstantial claim
  • Findingown data

    The increase in BLI flux was significantly attenuated when the cells were re-introduced to the no TTFields condition for 24 h.

    “but this increase was significantly attenuated when the cells were re-introduced to the no TTFields condition for 24 h (Fig. 7, two-way ANOVA, p < 0.005, TTFields [24 h] vs. TTFields [24 h] followed by no TTFields [24 h]).”
    Quote in the paperSubstantial claim
  • Findingown data

    TTFields augments membrane accessibility by compounds such as 5-aminolevulinic acid.

    “With TTFields, we present evidence showing augmented membrane accessibility by compounds such as 5-aminolevulinic acid, a reagent used intraoperatively to delineate tumor from normal tissue in glioblastoma patients.”
    Quote in the paperSubstantial claim
  • Findingown data

    TTFields significantly enhances the tumor to normal cell ratio for PpIX fluorescence brought on by 5-ALA exposure and uptake.

    “We show that TTFields significantly enhances the tumor to normal cell ratio for PpIX fluorescence (brought on by 5-ALA exposure and uptake), and in this manner, may better delineate tumor margins in intraoperative settings.”
    Quote in the paperSubstantial claim
  • May combine two claims. 17
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Findingown data

    In U87-MG cells seeded at high density, no TTFields samples showed densely matted, elongated and flattened membrane extensions, while after 24 h of TTFields exposure these structures were replaced by short, bulbous and bleb-like structures.

    “For no TTFields samples, the cell surface appeared to be covered in densely matted, elongated and flattened membrane extensions, similar to membrane ruffles and contiguous with the cellular membrane. In contrast, after 24 h of exposure to TTFields, the densely matted and elongated structures were replaced by short, bulbous and bleb-like structures.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Increases in bioluminescence and membrane hole production with TTFields exposure disappeared by 24 h after cessation of alternating electric fields, demonstrating that the phenomenon is reversible.

    “Further investigations showed that increases in bioluminescence and membrane hole production with TTFields exposure disappeared by 24 h after cessation of alternating electric fields thus demonstrating that this phenomenom is reversible.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the setting of TTFields, FITC-labeled dextrans resulted in an increase in influx of 4 kDa and 20 kDa dextrans but not 50 kDa dextrans.

    “The accessibility of the cell membrane to small probes in the setting of TTFields was tested with FITC-labeled dextrans, which resulted in an increase in influx of 4 kDa (Stokes’ radius ~1.4 nm44) and 20 kDa (Stokes’ radius ~3.3 nm44) but not 50 kDa dextrans (Stokes’ radius ~5 nm44).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A similar reversible pattern occurred with 4 kDa Dextran-FITC fluorescence: TTFields (24 h) significantly increased fluorescence compared to no TTFields, and this increase was significantly attenuated after 24 h of no TTFields.

    “and for 4 kDa Dextran-FITC fluorescence (Figure 12B, p < 0.05, two-way ANOVA, TTFields vs. no TTFields; and p < 0.05, TTFields vs. TTFields followed by no TTFields).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A similar reversible pattern occurred with PpIX fluorescence: TTFields (24 h) significantly increased PpIX fluorescence compared to no TTFields, and this increase was significantly attenuated after 24 h of no TTFields.

    “A similar pattern of reversible readouts occurred with PpIX fluorescence (Supplemental Figure S12A, p < 0.0005, two-way ANOVA, TTFields vs. no TTFields and p < 0.0004, TTFields vs. TTFields followed by no TTFields)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After 1 h of 200 kHz TTFields, there was significant uptake of 4 kDa and 20 kDa Dextran-FITC in U87-MG cells compared to no TTFields, but no significant difference for 50 kDa Dextran-FITC.

    “When U87-MG cells were subjected to 1 h of 200 kHz TTFields, there was a significant uptake of Dextran-FITC of molecular weights 4 kDa and 20 kDa, compared to no TTFields exposure, but there was no significant difference in uptake for 50 kDa Dextran-FITC (Fig. 3b–e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The increase in BLI occurred as early as 30 minutes after commencement of TTFields and continued to 24 h of TTFields exposure.

    “This increase in BLI occurred as early as 30 minutes after commencement of TTFields and continued to 24 h of TTFields exposure (Fig. 2a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TTFields exposure resulted in significantly increased uptake of 5-ALA into U87-MG/eGFP-fLuc cells as early as 6 h (p = 0.047) and this increase was maintained at 24 h (p = 0.011).

    “TTFields exposure resulted in significantly increased uptake of 5-ALA into U87-MG/eGFP-fLuc cells as early as 6 h of TTFields exposure (Fig. 4a, b, p = 0.047, Student’s t-test, TTFields vs. no TTFields) and this increase was maintained with prolonged TTFields exposure of 24 h (Fig. 4a, b, p = 0.011).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At TTFields exposure lengths of 0.5-3 h, the duration of BLI augmentation lasted about 5 min; at exposures of 12-25 h, the difference in BLI between TTFields and no TTFields conditions lasted for more than 20 min.

    “At lengths of TTFields exposure of 0.5–3 h, the duration in BLI augmentation (compared to no TTFields conditions) lasted about 5 min. However, at TTFields exposures of 12–25 h, this difference in BLI between TTFields and no TTFields conditions lasted for more than 20 min (Supplemental Figure S9A).”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    All experimental conditions were done in triplicate and statistical analysis was calculated via 2-way ANOVA.

    “All experimental conditions were done in triplicate and statistical analysis calculated via 2-way ANOVA.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Unless otherwise mentioned, all experiments were done in at least triplicate samples per condition and per time point.

    “Unless otherwise mentioned, all experiments were done in at least triplicate samples per condition and per time point.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    TTFields alters cellular membrane structure, rendering it more permeant to chemotherapeutics.

    “We show that TTFields also alters cellular membrane structure thus rendering it more permeant to chemotherapeutics.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The membrane holes observed by SEM are not artifacts of sample preparation and reflect actual holes in living cell membranes.

  • May combine two claims.

    Premisecitation

    TTFields compliance (≥75% vs. <75%) was an independent predictor of overall survival in the retrospective analysis of the full EF-14 trial dataset, and duration of TTFields use also affected overall survival.

    “TTFields compliance (≥75% vs. <75%) was an independent predictor of overall survival in the retrospective analysis of the full EF-14 trial dataset2 and the duration of use of TTFields was also found to affect overall survival60.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Stupp, R. et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318, 2306–2316 (2017). source

      Not checked in the free run.

    • cites [60] Ram, Z., Kim, C. Y., Nicholas, G. A. & Toms, S. A. ACTR-27. Compliance and treatment duration predict survival in a phase 3 EF-14 trial of tumor treating fields with temozolomide in patients with newly diagnosed glioblastoma. NeuroOncology 19(suppl_6), vi6–vi7 (2017).

      Not checked in the free run.

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

    Study design and conductnone given

    Coverslips from three experiments per condition were used, and at least 5 cells per coverslip were analyzed for hole count and size, in a double-blind manner.

    “Coverslips from three experiments per condition were used, and at least 5 cells per coverslip were analyzed for hole count and size, in a double-blind manner.”
    • Also stated in: § SEM shows that TTFields alters membrane morphology of U87-MG/eGFP-fLuc cells · plain
      “Coverslips from three experiments per condition were used, and at least 5 cells per coverslip were analyzed for hole count and size, in a double-blind manner”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    TTFields treatment in conjunction with Withaferin A synergistically inhibited the growth of human glioblastoma cells.

    “Recently we have demonstrated that TTFields treatment, in conjunction with a novel anticancer compound Withaferin A, synergistically inhibited the growth of human glioblastoma cells18.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Chang, E. et al. Synergistic inhibition of glioma cell proliferation by Withaferin A and tumor treating fields. J. Neurooncol. 134, 259–268 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    TTFields cause GBM cells to become more permeant to substances as large as 20 kDa, but no greater than 50 kDa.

    “This suggests that TTFields cause GBM cells to become more permeant to substances as large as 20 kDa, but no greater than 50 kDa.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    TTFields has been shown to prolong median survival by 5 months in glioblastoma patients on maintenance temozolomide chemotherapy.

    “Most recently, TTFields has been shown to prolong median survival (by 5 months) of glioblastoma patients on maintenance temozolomide chemotherapy2,9.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Stupp, R. et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318, 2306–2316 (2017). source

      Not checked in the free run.

    • cites [9] Stupp, R. et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA 314, 2535–2543 (2015). source

      Not checked in the free run.

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

    Premisecitation

    TTFields disrupts the localization of septins and thereby perturbs mitosis.

    “TTFields has been shown to disrupt the localization of septins (intracellular proteins responsible for anchoring mitotic spindles during cellular division) and thereby perturb mitosis14.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Gera, N. et al. Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit. PLoS ONE 10, e0125269 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Increased GBM cell permeability to D-luciferin as measured by BLI was not due to the effects of TTFields on luciferase itself, but rather due to an increased influx of D-luciferin into cells engineered to express firefly luciferase.

    “Increased GBM cell permeability to D-luciferin as measured by BLI was not due to the effects of TTFields on luciferase itself, but rather due to an increased influx of its substrate D-luciferin into the cells engineered to express the firefly luciferase.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    All ROI analyses were performed in a blinded manner in which neither the individual responsible for SEM image acquisition nor the one performing data analyses knew of the experimental conditions for the samples.

    “All ROI analyses were performed in a blinded manner in which neither the individual responsible for SEM image acquisition nor the one performing data analyses knew of the experimental conditions for the samples.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The work focused on glioblastoma cells using the 200 kHz TTFields frequency because FDA approval exists only for glioblastoma and only at this frequency.

    “In addition, we focused our work in glioblastoma cells using the 200 kHz TTFields frequency, because currently FDA approval exists only for glioblastoma and only at this frequency.”
    Quote in the paperSubstantial claim
21 of 21

  • The paper relies on this without support.

    The PCS-201 fibroblasts used are representative of normal human cells for assessing whether TTFields effects are cancer-specific.

    “In contrast to U87-MG cells, TTFields did not significantly alter the size nor the number of holes in normal human fibroblast cells (Fig. 6).”

  • The paper relies on this without support.

    The membrane holes observed by SEM are not artifacts of sample preparation and reflect actual holes in living cell membranes.

    “Finally, we present scanning electron microscopy (SEM) data that demonstrate an increase in the number and size of holes in glioblastoma cell membranes caused by TTFields exposure.”

  • The paper relies on this without support.

    This is the first study to report the effects of TTFields on cancer cellular membrane integrity.

    “To our knowledge, this is the first study to report the effects of TTFields on cancer cellular membrane integrity.”

  • The paper relies on this without support.

    TTFields exert their maximal antiproliferative effect on dividing cells.

    “TTFields exert their maximal antiproliferative effect on dividing cells”
4 of 4

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 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].”

    From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [27]

  • 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].”

    From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [27]

  • 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.”

    From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [27]

  • Even 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”

    From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [27]

  • The 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].”

    From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [27]

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.

  • Two molecular weights are given for 5-ALA

    Minor

    The same sentence gives 5-ALA a molecular weight of 167.6 g/mol and 169 Da. These are equivalent molecular-weight units, but 167.6 rounds to 168, not 169, at the stated whole-number precision.

  • Luciferase substrates are assigned in opposite orders

    Minor

    The background's use of "respectively" assigns d-luciferin to Renilla luciferase and coelenterazine to firefly luciferase. The methods assign d-luciferin to firefly luciferase and coelenterazine to Renilla luciferase.

  • Figure 4 caption disagrees on the second imaging time point

    Minor

    The caption describes the representative images as taken at 6 and 24 hours, but says their scale bar applies to 6- and 12-hour data.

  • Standard control incubator atmosphere differs between sections

    Minor

    The reversibility experiment describes standard, no-TTFields culture conditions as 95% oxygen, whereas the methods describe the no-TTFields control incubator as 95% air.

4 of 4

Cites

Flagged first, then by citations

Research works printed but not linked: 6

  1. Diego UoC-S. SRX2006411: GBM39 EC naive. 2016. https://www.ncbi.nlm.nih.gov/sra/SRX2006411[accn]
  2. JoVE Science Education Database. Basic Methods in Cellular and Molecular Biology (Passaging Cells, JoVE, Cambridge, MA, 2018).
  3. Strober, W. in Current Protocols in Immunology (John Wiley and Sons, New York, 2001), Appendix 3: Appendix3A.
  4. Giladi, M. et al. Mitotic spindle disruption by alternating electric fields leads to improper chromosome segregation and mitotic catastrophe in cancer cells. Sci. Rep. 5, 18046 (2015). · DOI · Paper page
  5. Pubchem. Molecular weight of firefly d-Luciferin. 2017. https://pubchem.ncbi.nlm.nih.gov/compound/D-Luciferin
  6. Pubchem. Molecular weight of coelentrazine. 2017. https://pubchem.ncbi.nlm.nih.gov/compound/2762722

Cited by

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Related

Authors
Chang, E., Patel, C. B., Pohling, C., Young, C., Song, J., Flores, T. A., Zeng, Y., Joubert, L.-M., Arami, H., Natarajan, A., Sinclair, R., & Gambhir, S. S.
Affiliations
  • Stanford Medicine (US)
  • Stellenbosch University (ZA)
Corresponding author
Gambhir, Sanjiv S.
ORCID
Venue
Cell Death Discovery
Publisher
Springer Science and Business Media LLC
Published
2018-12-05
Volume
4
Issue
1
Pages
113-113
ISSN
2058-7716 (ISSN-L)
DOI
10.1038/s41420-018-0130-x
PMC
PMC6281619
OpenAlex
W2902560780
Cited by
137
References
57
Citations by year
2026: 9 · 2025: 13 · 2024: 26 · 2023: 25 · 2022: 24 · 2021: 21 · 2020: 17 · 2019: 2
FWCI
5.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death Discovery (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Ben and Catherine Ivy Foundation
  • Ludwig Institute for Cancer Research
  • Novocure
  • National Cancer Institute (T32CA009695)
  • Stanford Cancer Institute
Topics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Inactivation Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
Keywords
tumor treating fields, glioblastoma, membrane permeability, AC electric field, 5-aminolevulinic acid, chemotherapy delivery, combination therapy, bioluminescence

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