Cold Atmospheric Plasma and Plasma-Activated Medium: Antitumor Cell Effects with Inherent Synergistic Potential

摘要

Nitrite and H2O.,, long-lived molecular species from cold atmospheric plasma (CAP) and plasma-activated medium (PAM), reach tumor target cells in vitro and in vivo. Through several steps, the interaction between nitrite and H^OJeads to generation of singlet oxygen ('CO. 'O., then interacts with a specific biochemical switchboard on tumor cells that is composed of cat-alase, superoxide dismutase (SOD), first aptosis signal (FAS) receptor, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. As a result, local inactivation of catalase by minute concentrations of primary singlet oxygen opens a strong autoamplificatory sustained process of secondary singlet oxygen generation and catalase inactivation. This process is driven by tumor cell-specific NADPH oxidase-1 and spreads within the tumor cell population. The concerted action of singlet oxygen interaction with catalase, SOD, and FAS receptor causes an efficient mode of synergistic interaction. Defined reactive oxygen and reactive nitrogen species (ROS/RNS) such as H2O, and nitrite have multiple functions in this process. Catalase-mediated oxidation of nitrite enhances generation of nitrogen dioxide, which is rate limiting for singlet oxygen generation. Before singlet oxygen-mediated inactivation of catalase and, subsequently, reactivated intercellular ROS/RNS signaling can activate the mitochondrial pathway of apoptosis, counteraction of glutathione to lipid peroxidation must be abrogated through aquaporin-mediated influx of H2O2 into cells. CAP- and PAM-dependent immunogenic cell death triggers a strong immune response that finalizes antitumor action in vivo. Thus, the high efficiency of CAP and PAM seem to depend on concerted action of several dominant steps and their autoamplificatory potential.