title: Singlet oxygen treatment of tumor cells triggers extracellular singlet oxygen generation, catalase inactivation and reactivation of intercellular apoptosis-inducing signaling.
abstract: Intracellular singlet oxygen generation in photofrin-loaded cells caused cell death without discrimination between nonmalignant and malignant cells. In contrast, extracellular singlet oxygen generation caused apoptosis induction selectively in tumor cells through singlet oxygen-mediated inactivation of tumor cell protective catalase and subsequent reactivation of intercellular ROS-mediated apoptosis signaling through the HOCl and the NO/peroxynitrite signaling pathway. Singlet oxygen generation by extracellular photofrin alone was, however, not sufficient for optimal direct inactivation of catalase, but needed to trigger the generation of cell-derived extracellular singlet oxygen through the interaction between H2O2 and peroxynitrite. Thereby, formation of peroxynitrous acid, generation of hydroxyl radicals and formation of perhydroxyl radicals (HO2(.)) through hydroxyl radical/H2O2 interaction seemed to be required as intermediate steps. This amplificatory mechanism led to the formation of singlet oxygen at a sufficiently high concentration for optimal inactivation of membrane-associated catalase. At low initial concentrations of singlet oxygen, an additional amplification step needed to be activated. It depended on singlet oxygen-dependent activation of the FAS receptor and caspase-8, followed by caspase-8-mediated enhancement of NOX activity. The biochemical mechanisms described here might be considered as promising principle for the development of novel approaches in tumor therapy that specifically direct membrane-associated catalase of tumor cells and thus utilize tumor cell-specific apoptosis-inducing ROS signaling.
authors.affiliation: Institute of Virology, Department of Medical Microbiology and Hygiene, University Medical Center, Freiburg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Riethmüller
authors.affiliation: Institute of Virology, Department of Medical Microbiology and Hygiene, University Medical Center, Freiburg, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Burger
authors.affiliation: Institute of Virology, Department of Medical Microbiology and Hygiene, University Medical Center, Freiburg, Germany. Electronic address: georg.bauer@uniklinik-freiburg.de.
authors.forename: Georg
authors.initials: G
authors.lastname: Bauer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002374:Catalase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D017323:Dihematoporphyrin Ether / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006997:Hypochlorous Acid / Q000378:metabolism; D008027:Light; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D017319:Photosensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction; D026082:Singlet Oxygen / Q000378:metabolism / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D013654:Taurine / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: C466420:5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride; D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D017319:Photosensitizing Agents; D013450:Sulfones; D019014:fas Receptor; D030421:Peroxynitrous Acid; D026082:Singlet Oxygen; D013654:Taurine; D009569:Nitric Oxide; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D006997:Hypochlorous Acid; D017323:Dihematoporphyrin Ether; D006861:Hydrogen Peroxide; D002374:Catalase; D019255:NADPH Oxidases; C505530:CASP8 protein, human; D053181:Caspase 8
keywords: Catalase; Intercellular apoptosis-inducing signaling; Nitric oxide; Peroxnitrite; Photodynamic therapy; Singlet oxygen