Dividing Cells are Most Susceptible to Targeted Osmotic Lysis Cancer Therapy

Abstract

Voltage‐gated sodium channels (VGSCs) are upregulated in aggressive carcinomas, making these channels a target for novel clinical therapies. Targeted Osmotic Lysis (TOL) is a novel cancer therapy that combines pharmacologically blocking Na+,K+, ATPase (sodium pumps) while stimulating VGSCs with a pulsed electric field. The consequent increase in intracellular Na+ causes an osmotic lysis of the cells that overexpress VGSCs. Noncancerous cells, with fewer VGSCs do not lyse. We hypothesized that variability in efficacy of TOL is due to VGSC expression that varies across the cell cycle. We assessed cell surface expression of VGSCs and Na+,K+‐ATPase during phases of the cell cycle in which there are single copies of DNA compared with phases in which DNA has doubled. For this, DNA was labeled with either propidium iodide (PI) or DAPI and VGSCs were labeled with a pan‐specific VGSC antibody while Na+,K+‐ATPases were labelled with a pan‐specific Na+,K+‐ATPase antibody in eight immortalized cancer and non‐cancer cell lines. With flow cytometry we showed that VGSC expression doubled during phases of cell division (S‐M phases) compared to G0‐G1 phases, whereas Na+,K+‐ATPase expression increased by 1.5‐fold. To investigate whether cells in S‐M phases are more susceptible to TOL due to the increase in VGSCs, cells were treated and immediately fixed and stained with PI for cell cycle analysis. There was a 30% decrease in the percentage of total cells that were treated with TOL compared to cells that did not receive TOL treatment. This finding is evidence that dividing cells are more susceptible to TOL than cells in G0‐G1 phases. It is thus likely that combined therapies will likely lead to better patient outcomes.