Permeabilizing Cell Membranes with Electric Fields

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.

Keywords: alternating electric fields (AEFs), bioelectrorheology; cancer; cell membrane; cell modeling; electroporation; glioblastoma; tumor treating fields (TTFields); voltage-gated ion channel.

Figure 1

Effective working frequency ranges of voltage-gated calcium channels, tumor treating fields (TTFields), the bioelectrorheological model, and the electroporation model along the electromagnetic spectrum. As shown in the figure, TTFields falls within the range of intermediate frequencies while calcium channels operate at very low frequencies. By way of contrast, electroporation usually operates within the radio frequency ranges (television, radio, cell phones, microwave) while the bioelectrorheological model spans intermediate to radio frequencies.

Figure 2

(A) Standard mechanism of action of TTFields in cancer cells by disrupting mitotic spindle formation (B) TTFields disrupting cancer cell plasma membranes resulting in increased permeability.

Figure 3

The three models that could partially explain the action of alternating electric fields (AEFs) on cell membrane integrity and function include: (A) Impact of AEFs on voltage-gated ion channels (adapted from [38,39]). (B) The bioelectrorheological model (adapted from [40]). (C) The electroporation model (reprinted with permission from ref. [41]. Copyright 2019 Springer Nature). Parameters are defined in the respective references and Tables S1–S3.

Figure 4

The bioelectrorheological model in which exogenously applied electric fields may shape deformations and destabilize membranes, which can contribute to electroporation and other electric field-induced cell phenomena including electrofusion and electro-destruction.

Figure 5

Illustration of the two main types of electroporation (direct current [DC] and alternating current [AC]) and their effects on a cell and its membrane. DC involves the use of short, individual pulses of electric charge whereas AC applies electric charge in an oscillating motion (increasing and decreasing) over a period of time. The dark blue circles represent molecules (average Stokes diameter ~20 nm [64]) that can only enter the cell through pores in the membrane. E is the electric field intensity (units V/cm) and E_crit is the minimum field intensity required to reach the cell’s membrane potential threshold. The diagram shows how E can impact the cell’s survival depending on the type of current (DC or AC) and whether E is greater or less than the critical field intensity (E_crit). When E < E_crit, the effects of electroporation are reversible, and the cell remains viable.