Signal amplification by tumor cells: Clue to the understanding of the antitumor effects of cold atmospheric plasma and plasma-activated medium

The expression of membrane-associated catalase, SOD, and NADPH oxidase represents a characteristic feature of tumor cells and a novel target for tumor therapy. An analytical approach, based on experimentally determined responses of cells from distinct steps of oncogenesis toward defined reactive oxygen/nitrogen species (ROS/RNS) is presented. It is suggested that singlet oxygen from cold atmospheric plasma (CAP) or plasma-activated medium (PAM) triggers tumor cells to generate high concentrations of secondary singlet oxygen that inactivates their protective catalase. This reactivates intercellular ROS/RNS-dependent apoptosis-inducing signaling and also may lead to aquaporin-mediated influx of extracellular H2O2. Initial targeting of either catalase, SOD or of the FAS receptor by CAPor PAM-derived singlet oxygen causes the same final effect. The generation of singlet oxygen is based on a complex interaction between H2O2 and peroxynitrite. HOCl and peroxynitrite are also potentially involved in the modulation of immunogenic cell death and thus trigger a cytotoxic T cell response that acts synergistically with the primary ROS/RNS-related effects induced by CAP or PAM. This approach might be useful to define optimal composition of CAP, to define selective CAP and PAM action, to allow for the establishment of synergistic effects and to link CAPand PAMrelated ROS/RNS effects on apoptosis with immunogenic cell death.