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. 2019 Sep 26;9:13931. doi: 10.1038/s41598-019-50329-3

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Apoptosis induction by CAP/PAM is mediated by the generation of primary and secondary singlet oxygen (¹O₂). NADPH oxidase 1 (NOX1) is expressed in the membrane of tumor cells and generates extracellular superoxide anions (O₂^●−) (#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 RONS-mediated signaling. Comodulatory SOD (#5) is required to prevent O₂^●−-mediated inhibition of catalase. Further important elements in the membrane are the FAS receptor (#6), Dual oxidase (DUOX) (#7), from which a peroxidase domain (POD) is split through matrix metalloprotease, proton pumps (#8) and aquaporins (#9). H₂O₂ and NO₂⁻ derived from CAP treatment and stable in PAM interact and generate peroxynitrite (ONOO⁻) (#10). In the vicinity to membrane-associated proton pumps ONOO⁻ is protonated to peroxynitrous acid (ONOOH) (#11) and decomposes into ^●NO₂ and ^●OH radicals (#12). ^●OH radicals react with H₂O₂, resulting in the formation of hydroyperoxyl radicals (HO₂^●) (#13). The subsequent generation of peroxynitric acid (O₂NOOH) (#14) and peroxynitrate (O₂NOO⁻) (#15) allows for the generation of “primary singlet oxygen” (¹O₂) (#17). Primary ¹O₂ causes local inactivation of membrane-associated catalase (#18). Surviving H₂O₂ and ONOO⁻ at the site of inactivated catalase are the source for sustained generation of “secondary ¹O₂” through reactions #19- #24. Secondary ¹O₂ may either inactivate further catalase molecules (#25) and thus trigger autoamplification of ¹O₂ generation (#29), or activate the FAS receptor (#26) and in this way enhance the activities of NOX1 and NOS. This enhances the efficiency of secondary ¹O₂ generation. The site of action of specific inhibitors and scavengers are indicated. Please find details on the elements on the surface of tumor cells in references^{74,80,97,118,124,125,130}, on singlet oxygen generation in references^59,96,97,118, and on intercellular apoptosis-inducing signaling after catalase inactivation in references^78,80,83,132.