Permeabilizing Cell Membranes with Electric Fields

Our plain-English summary of Permeabilizing Cell Membranes with Electric Fields, by A.A. Aguilar, M.C. Ho, E. Chang, et al (Cancers, 2021).

The study

• Authors: A.A. Aguilar, M.C. Ho, E. Chang, K.W. Carlson, A. Natarajan, T. Marciano, Z. Bomzon, C.B. Patel
• Journal: Cancers
• Published: 2021;13(9)
• Type of article: Review
• Cited by: 49 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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

In plain English

This article was a review, not an original study, and did not study asbestos exposure or any workers or patients. It covered published research on tumor treating fields (TTFields), alternating electric fields applied to tumors, and how they might make cancer cell membranes more permeable. As background, the review noted that in 2019, 150 kHz TTFields received FDA approval under a humanitarian device exemption for first-line treatment of unresectable, locally advanced or metastatic malignant pleural mesothelioma, combined with pemetrexed and platinum-based chemotherapy. In the single-arm phase II trial it cited, median overall survival was 18.2 months and median progression-free survival was 7.6 months. The authors reviewed three possible explanations: voltage-gated ion channels, a bioelectrorheological model, and electroporation. They noted that TTFields' frequencies (100 to 500 kHz) and field strengths (1 to 4 V/cm) often do not match those of the three models. The authors concluded that ion channels alone do not explain the effects, and that a combination of the bioelectrorheological and electroporation models most likely does. They noted that most computational models are based on single cells in isolation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: narrative review of the literature on how alternating electric fields (TTFields) affect cell membranes, with theoretical discussion
• Who was studied: no human population studied; the review covered published cell, modeling and clinical studies of TTFields and three proposed explanatory models
• Exposure: not asbestos; the exposure discussed was intermediate-frequency alternating electric fields used as cancer treatment (TTFields)
• Main results:
  • Background reported by the review (not its own finding): in 2019, 150 kHz TTFields received FDA approval under a humanitarian device exemption
  • The approval was for first-line treatment of unresectable, locally advanced or metastatic malignant pleural mesothelioma, with TTFields combined with pemetrexed and platinum-based chemotherapy
  • In the cited single-arm phase II trial in malignant pleural mesothelioma (another study's result), median overall survival was 18.2 months and median progression-free survival was 7.6 months
  • The authors judged voltage-gated calcium channels too small to account for the membrane pores reported after TTFields exposure
  • The bioelectrorheological modeling reviewed used a field strength of 250 V/cm, two orders of magnitude greater than that of TTFields (1 to 4 V/cm)
  • The therapeutic frequency and field-strength ranges of TTFields often did not overlap with those of the three proposed models
  • Modeling by two co-authors (cited as personal communication) predicted that electric field lines concentrate between contact points of closely packed cells
• The authors' conclusion: The authors concluded that the effect of these electric fields on cancer cell membranes is most likely explained by a combination of the bioelectrorheological and electroporation models, not by calcium channels alone
• Limitations the authors state:
  • The field strengths in the bioelectrorheological studies reviewed were far higher than those of TTFields
  • Differences in field intensity, frequency and duration limit how far electroporation can be compared with TTFields
  • Most computational models are based on isolated single cells

Topics

Medical terms in this study, explained in our Lexicon: Tumor Treating Fields (TTFields), Mesothelioma.

Related studies

• Tumor Treating Fields (TTFields) Hinder Cancer Cell Motility through Regulation of Microtubule and Acting Dynamics — T. Voloshin, R.S. Schneiderman, et al. (2020)
• The Mechanisms of Action of Tumor Treating Fields — J.C. Moser, E. Salvador, et al. (2022)
• Mortality from amyotrophic lateral sclerosis, other chronic disorders, and electric shocks among utility workers — C. Johansen, J.H. Olsen (1998)
• Real-Time Monitoring of the Effect of Tumour-Treating Fields on Cell Division Using Live-Cell Imaging — H.T. Le, M. Staelens, et al. (2022)
• The crocidolite fibres interaction with human mesothelial cells as investigated by combining electron microscopy, atomic force and scanning near-field optical microscopy — L. Andolfi, E. Trevisan, et al. (2013)
• Tumor treating fields affect mesothelioma cell proliferation by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations — L. Mannarino, F. Mirimao, et al. (2022)

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