The synergistic effect between hydrogen peroxide and nitrite, two long-lived molecular species from cold atmospheric plasma, triggers tumor cells to induce their own cell death

Nitrite and H(2)O(2) are long-lived species in cold atmospheric plasma and plasma-activated medium. It is known that their synergistic interaction is required for selective apoptosis induction in tumor cells that are treated with plasma-activated medium. This study shows that the interaction between nitrite and H(2)O(2) leads to the formation of peroxynitrite, followed by singlet oxygen generation through the interaction between peroxynitrite and residual H(2)O(2). This primary singlet oxygen causes local inactivation of few catalase molecules on the surface of tumor cells. As a consequence, H(2)O(2) and peroxynitrite that are constantly produced by tumor cells and are usually decomposed by their protective membrane-associated catalase, are surviving at the site of locally inactivated catalase. This leads to the generation of secondary singlet oxygen through the interaction between tumor cell-derived H(2)O(2) and peroxynitrite. This selfsustained process leads to autoamplification of secondary singlet oxygen generation and catalase inactivation. Inactivation of catalase allows the influx of H(2)O(2) through aquaporins, leading to intracellular glutathione depletion and sensitization of the cells for apoptosis induction through lipid peroxidation. It also allows to establish intercellular apoptosis-inducing HOCl signaling, driven by active NOX1 and finalized by lipid peroxidation through hydroxyl radicals that activates the mitochondrial pathway of apoptosis. This experimentally established model is based on a triggering function of CAP and PAM-derived H(2)O(2)/nitrite that causes selective cell death in tumor cells based on their own ROS and RNS. This model explains the selectivity of CAP and PAM action towards tumor cells and is in contradiction to previous models that implicated that ROS/RNS from CAP or PAM were sufficient to directly cause cell death of tumor cells.