1 September 2003 Chain-breaking Antioxidant and Cytoprotective Action of Nitric Oxide on Photodynamically Stressed Tumor Cells
Magdalena Niziolek, Witold Korytowski, Albert W. Girotti
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Nitric oxide (NO) has a multitude of physiological roles, including the ability to protect cells against oxidant-induced killing, e.g. by inhibiting caspase-mediated apoptosis or by intercepting damaging free radicals derived from membrane lipids. The purpose of this study was to test the hypothesis that low flux NO acting in the latter fashion can enhance tumor-cell resistance to photodynamic killing, specifically that sensitized by 5-aminolevulinic acid (ALA)–derived protoporphyrin IX (PpIX). Preliminary model experiments with iron-ascorbate–treated, PpIX-sensitized liposomes showed that spermine NONOate (SPER/NO)–derived NO had no effect on photoinduced accumulation of primary singlet oxygen adducts, e.g. the cholesterol hydroperoxide 5α-OOH, but dose-dependently inhibited the buildup of free radical–generated oxidation products arising from one-electron turnover of primary peroxides. In subsequent studies, breast tumor COH-BR1 cells in serum-free medium were treated with 1 mM ALA for 15 min and then without ALA for 3.75 h, allowing biogenerated PpIX to diffuse to extramitochondrial sites, including plasma membrane. Cells were irradiated in the absence or presence of SPER/NO and compared for peroxidative damage and Hoechst-assessed viability after 5 h in the dark. Iron-stimulated necrotic photokilling and accumulation of chain lipid peroxidation products were observed, and this was inhibited strongly by SPER/NO, but not by decomposed SPER/NO, confirming that NO was the active agent. When introduced after irradiation, NO became progressively less inhibitory, consistent with ongoing but waning free-radical activity. These findings provide new insights into the possible role of NO in tumor resistance to ALA–photodynamic therapy and other photodynamic treatments.

Magdalena Niziolek, Witold Korytowski, and Albert W. Girotti "Chain-breaking Antioxidant and Cytoprotective Action of Nitric Oxide on Photodynamically Stressed Tumor Cells," Photochemistry and Photobiology 78(3), 262-270, (1 September 2003). https://doi.org/10.1562/0031-8655(2003)078<0262:CAACAO>2.0.CO;2
Received: 12 February 2003; Accepted: 1 May 2003; Published: 1 September 2003

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