Chapter 2 │ Page 54 to interfere with cellular redox homeostasis and induce NTP sensitization (Figure 4). More detailed investigation into the underlying cause revealed that the enhanced responsiveness to NTP is not associated with changes in cellular morphology or a higher proliferative capacity, as previously suggested in literature, but potentially with a higher baseline intracellular ROS level (Figure 5, Appendix C). It is important to note that cytotoxicity from the fluorescent dyes used here was considered negligible, as the working concentrations were previously optimized and high cell survival was demonstrated for untreated controls in every experiment (SC263/T-PL/PH). In addition to reactive chemical species being generated by NTP, di erent physical factors, including electric fields, ultraviolet (UV) radiation, and thermal changes, are produced. These physical factors could also interact with, and influence the biological samples during NTP treatment, especially with the DBD system. In the past, detailed electrical and energy characterizations of DBD devices were performed by di erent labs, including our lab with our device, to ensure the delivery of an electrically and thermally stable plasma [31, 32, 35, 36]. In addition, several studies have already demonstrated that neither global and local electric fields, nor physical factors (e.g. UV radiation, thermal damage) originating from NTP treatment contribute to the induction of cell death [37-39]. Indeed, Lin et al., have reported that DBD plasma discharged in pure nitrogen did not induce cell death for multiple cancer types. In this setting, cells were exposed to UV radiation, global pulsed-electric fields, and local electric fields and temperature changes from streamers and filaments [37, 38]. Taken together, it is clear that the reactive oxygen species were the main biological e ectors, and in our similar system, theses physical components had minimal e ect on cancer cell death. It has long been hypothesized that increased vulnerability of certain cells towards NTP is a result of di erent cell types displaying a diverse range of redox profiles. In fact, certain cancer cells exhibit higher intracellular ROS levels at a basal state and
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