Permeabilizing Cell Membranes with Electric Fields

SIMPLE SUMMARY: The FDA recently approved a fourth approach (in addition to surgery, radiation therapy, and chemotherapy) for treating glioblastoma; namely, tumor treating fields (TTFields), a form of alternating electric fields (AEF) therapy that is delivered to the tumor via electrodes placed on the scalp. Despite prolonging overall survival by 5 months when combined with standard chemotherapy in patients with newly diagnosed glioblastoma, the mechanisms of action of TTFields are not fully understood and primarily involve its interruption of mitotic spindle formation which impairs cancer cell division. A novel mechanism of action of TTFields at the cell membrane was recently identified, in which TTFields increases cancer cell membrane permeability. This finding could be exploited to enhance drug delivery to cancer cells. Here, we review the likely mechanisms by which TTFields permeabilize cancer cell membranes, i.e., voltage-gated ion channels, bioelectrorheological effects, and electroporation. Finally, we discuss an explanatory formulation that incorporates all three models. 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.