Transcriptional Pathways Predisposing to Cancer Oxidative Stress Sensitivity and Resistance Are Shared Between Hydrogen Peroxide and Cold Gas Plasma but Not Hypochlorous Acid

Oxidative stress is universal to all cell types, including cancer. It is elicited by a surplus of reactive oxygen species (ROS) or a reduced cellular ability to defend against those. At low levels (oxidative eustress), this induces altered cellular signaling, while at higher levels (oxidative distress), cellular toxicity and non-specific redox signaling become apparent. While oxidation-induced cell death is a hallmark of many cancer therapies, including ROS-producing radiotherapy, some chemotherapies and targeted therapies, photodynamic therapy, and recently emerging physical modalities such as medical gas plasma (a multi-ROS generating technology), less is known about the transcriptional profiles predisposing cancer cells to oxidative demise. In particular, which genes are associated with resistance or sensitivity to ROS overload and subsequent toxicity has not been systematically investigated. Moreover, it is unclear if there are differences between oxidant types, such as hydrogen peroxide and hypochlorous acid. To this end, we here employed 35 cell lines of various origins (e.g., adenocarcinoma, melanoma, leukemia, squamous cell carcinoma, and neuroblastoma). We first performed in-house transcriptomic analysis to assess baseline transcriptional profiles. Second, all cell lines were exposed to four different ROS concentrations of either hydrogen peroxide, hypochlorous, or gas plasma exposure. Third, correlation analysis was performed to identify genes associated with (i) oxidative stress sensitivity, (ii) oxidative stress resistance, and (iii) similarities and/or differences between the different oxidative stress inducers. Intriguingly, distinct gene sets were found for all treatments, and there was a striking difference between hydrogen peroxide and hypochlorous acid, suggesting different modes of action of both oxidants.