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Nitric Oxide Inhibition of Chain Lipid Peroxidation Initiated by Photodynamic Action in Membrane Environments

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Abstract

Iron-catalyzed, free radical-mediated lipid peroxidation may play a major role in tumor cell killing by photodynamic therapy (PDT), particularly when membrane-localizing photosensitizers are employed. Many cancer cells exploit endogenous iNOS-generated NO for pro-survival/expansion purposes and for hyper-resistance to therapeutic modalities, including PDT. In addition to inhibiting the pro-oxidant activity of Fe(II) via nitrosylation, NO may intercept downstream lipid oxyl and peroxyl radicals, thereby acting as a chain-breaking antioxidant. We investigated this for the first time in the context of PDT by using POPC/Ch/PpIX (100:80:0.2 by mol) liposomes (LUVs) as a model system. Cholesterol (Ch or [14C]Ch) served as an in-situ peroxidation probe and protoporphyrin IX (PpIX) as photosensitizer. PpIX-sensitized lipid peroxidation was monitored by two analytical methods that we developed: HPLC-EC(Hg) and HPTLC-PI. 5α-hydroperoxy-Ch (5α-OOH) accumulated rapidly and linearly with irradiation time, indicating singlet oxygen (1O2) intermediacy. When ascorbate (AH–) and trace lipophilic iron [Fe(HQ)3] were included, 7α/7β-hydroperoxy-Ch (7-OOH) accumulated exponentially, indicating progressively greater membrane-damaging chain lipid peroxidation. With AH–/Fe(HQ)3 present, the NO donor SPNO had no effect on 5α-OOH formation, but dose-dependently inhibited 7-OOH formation due to NO interception of chain-carrying oxyl and peroxyl radicals. Similar results were obtained when cancer cells were PpIX/light-treated, using SPNO or activated macrophages as the NO source. These findings implicate chain lipid peroxidation in PDT-induced cytotoxicity and NO as a potent antagonist thereof by acting as a chain-breaking antioxidant. Thus, unless NO formation in aggressive tumors is suppressed, it can clearly compromise PDT efficacy.

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Abbreviations

PDT:

photodynamic therapy

NO:

nitric oxide

iNOS:

inducible nitric oxide synthase

Ch:

cholesterol

LOOH:

lipid hydroperoxide

5α-OOH:

5α-hydroperoxy cholesterol

7-OOH:

7α/7β-hydroperoxy cholesterol

ChOX:

oxidized cholesterol species

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Acknowledgements

Studies in the authors’ laboratories were supported by USPHS Grants CA72630, TW001386, and CA70823 (to AWG) and by Polish National Center for Science Grants NCN-2014/13/B/NZ3/00833 and 2017/27/B/NZ5/02620 (to WK). We thank Magdalena Niziolek, Mariusz Zareba, Peter Geiger, Andrew Vila, Vlad Levchenko, Tamas Kriska, and Jerzy Bazak for their many valuable contributions to the research supported by these grants.

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  1. Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA

    Albert W. Girotti

  2. Department of Biophysics, Jagiellonian University, Krakow, Poland

    Witold Korytowski

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Girotti, A.W., Korytowski, W. Nitric Oxide Inhibition of Chain Lipid Peroxidation Initiated by Photodynamic Action in Membrane Environments. Cell Biochem Biophys 78, 149–156 (2020). https://doi.org/10.1007/s12013-020-00909-2

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