ET-47TRIFLOUROPROMAZINE AN APPROVED ANTIPSYCHOTIC DRUG ENHANCES TUMOR TREATING FIELDS TREATMENT EFFICACY IN VITRO

摘要

Tumor Treating Fields (TTFields) are low intensity, intermediate frequency alternating electric fields that disrupt proper spindle microtubules arrangement thus leading to mitotic arrest and subsequent cancer cell death. TTFields treated cells could escape cell death by exiting mitosis and entering interphase without chromosome segregation or cell division, a process also known as mitotic slippage. Triflouropromazine (TFP) is a clinically approved antipsychotic drug of the phenothiazine class that was recently reported to display anti slippage properties. The aim of this work is to determine whether TFP could increase TTFields efficacy based on its anti slippage properties. For this purpose, cell survival, volume and clonogenic potential of human glioblastoma (U87, U118) and breast adenocarcinoma (MCF-7, MDA-MB-231) cell lines were assessed following treatment with TTFields (3 V/cm) with cell line specific optimal frequency, with or without TFP. The percentage of cells that underwent mitotic slippage was determined using immunofluorescence imaging. TTFields as single application lead to a significant decrease in cell counts (26-44% reduction of control) and to cell volume increase (113-127% of control) in all cell lines. While TFP treatment as single agent had no effect on cell growth or cell volume, the combined treatment of TTFields and TFP resulted in an additional decrease in cell counts (31-58% reduction of control), further increase in cell volume (122-162% of control) and a reduced clonogenic potential. Immunofluorescence images of cells treated with TTFields demonstrated a significant increase in the number of cells that underwent slippage as compared to control cells or cells treated with TFP. Surprisingly, cells treated with TTFields and TFP demonstrated no decrease in the number of cells that underwent slippage. These results suggest that TFP enhances TTFields efficacy not by the inhibition of mitotic slippage. Further studies are underway in order to reveal the mechanism underlying the enhanced effect.