Fig. 16.

Primary and secondary singlet oxygen triggered by H₂O₂ and nitrite in contact with tumor cells. A. NADPH oxidase 1 (NOX1) is expressed in the membrane of malignant cells and generates extracellular superoxide anions (#1). NO synthase (NOS) (#2) generates NO which can be either oxidated by NO dioxygenase (NOD) (#3) or pass through the cell membrane. Membrane-associated catalase (#4) protects tumor cells towards intercellular ROS/RNS-mediated signaling through decomposition of H₂O₂ and peroxynitrite, as well as oxidation of NO (not shown in the figure). Comodulatory SOD (#5) is required to prevent superoxide anion-mediated inhibition of catalase. Further important elements in the membrane are the FAS receptor (#6), Dual oxidase (DUOX) (#7), from which a peroxidase (POD) domain is split through matrix metalloprotease (MMP), proton pumps (#8) and aquaporins (#9). The interaction between H₂O₂ and nitrite (#10) leads to the generation of primary singlet oxygen (#11 - #19). Primary singlet oxygen (#19) causes local inactivation of catalase. As H₂O₂ and peroxynitrite are not decomposed at the site of inactivated catalase, these two species interact and generate secondary singlet oxygen (reactions # 20- #25). Secondary singlet oxygen can inactivate further catalase molecules (#26) and in this way promote autoamplificatory generation of secondary singlet oxygen/catalase inactivation, or activate the FAS receptor (#27), which leads to an enhancement of the activities of NOX1 and NOS (#28, 29). This enhancement is necessary for efficient generation of secondary singlet oxygen. B. Inhibition of NOX1 by AEBSF prevents the generation of secondary singlet oxygen and thus allows to study the generation of primary singlet oxygen and the induction of its signature specifically.