Abstract
INTRODUCTION
Tumor Treating Fields (TTFields) are intermediate frequency, alternating electric fields with anti-mitotic effects on cancerous cells. TTFields are delivered non-invasively through arrays placed on the skin at the tumor region. TTFields therapy is approved in several territories for treatment of glioblastoma (GBM) and mesothelioma. Recently, TTFields have been shown to increase GBM cell membrane permeability. The current study aimed to explore this effect in multiple cell lines and examine the potential benefits of combining TTFields with other anticancer agents.
METHODS
TTFields were delivered to GBM (U-87 MG), uterine sarcoma (MES-SA), and breast adenocarcinoma (MCF-7) cell lines for 72hr across a range of frequencies (50-500kHz). Cytotoxicity of TTFields was examined by cell counts, and intracellular accumulation of 7-aminoactinomycin D (7-AAD) was measured by flow cytometry. Exposing the cells to 7-AAD at different time points relative to TTFields application cessation was used to determine the kinetics of cell membrane permeability. The potential of TTFields to facilitate intracellular accumulation of anthracycline chemotherapeutics was tested in chemotherapy-sensitive and chemotherapy-resistant cells.
RESULTS
Elevated intracellular accumulation of 7-AAD was observed in all examined cell lines treated with TTFields, at an optimal frequency that differed from that for maximal TTFields-induced cytotoxicity. No intracellular accumulation of 7-AAD was seen for measurements performed after termination of TTFields application, indicating that increased cell membrane permeability by TTFields was temporary and reversible. Lastly, the accumulation of chemotherapeutic agents in chemotherapy-resistant cancer cells was elevated to the same extent as in matched chemotherapy-sensitive cells when TTFields were delivered concomitant with chemotherapy.
CONCLUSIONS
TTFields increased cancer cell permeability in a transient and reversible manner across multiple cancer cell types. The increased permeability enhanced intracellular accumulation of chemotherapeutics, even within chemotherapy-resistant cells.
Tumor treating fields increases membrane permeability in glioblastoma cells
