Resonance versus linear responses to alternating electric fields induce mechanistically distinct mammalian cell death

• AC fields induced cancer cell death via distinct frequency-dependent mechanisms.
• Death due to field-induced loss of surface adhesion exhibited resonance features.
• Death due to field-induced prolonged mitotic arrest exhibited a linear response.
• The two response mechanisms were quantitatively modeled and simulated.

Alternating electric (AC) fields are known to activate tumor cell death, but the underlying cellular mechanisms are poorly understood. We thus combined live-cell imaging with computational modeling to investigate the dynamic interactions between AC fields and cultured mammalian cells. Our results showed extensive cell death activated via two distinct mechanisms. At frequency range of 100–300 kHz and 800–1000 kHz, AC fields triggered prolonged mitotic arrest followed by apoptosis, and the cell death kinetics showed linear dependence on both field frequency and intensity. However, at intermediate frequencies, from 300 kHz to 800 kHz, cells died as a result of field-induced surface detachment, and the process exhibited a resonance frequency. Based on models of induced dielectric polarization and charge oscillation, we simulated the functional dependence of cell death kinetics on field frequency and intensity for both the linear and resonance response regimes. By comparing the simulated and experimental results, we not only determined the crucial electrical properties of mammalian cells that govern their interaction with AC fields but also acquired novel mechanistic understanding of the resulting cell death processes, which provides important new insight for potentially utilizing AC fields as an alternative anti-tumor remedy.