Journal
CELL BIOCHEMISTRY AND BIOPHYSICS
Volume 78, Issue 2, Pages 149-156Publisher
HUMANA PRESS INC
DOI: 10.1007/s12013-020-00909-2
Keywords
Nitric oxide; Inducible; Lipid-derived free radicals; Chain lipid peroxidation; Photodynamic action; Cholesterol hydroperoxides
Funding
- USPHS [CA72630, TW001386, CA70823]
- Polish National Center for Science [NCN-2014/13/B/NZ3/00833, 2017/27/B/NZ5/02620]
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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 [C-14]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. 5 alpha-hydroperoxy-Ch (5 alpha-OOH) accumulated rapidly and linearly with irradiation time, indicating singlet oxygen (O-1(2)) intermediacy. When ascorbate (AH(-)) and trace lipophilic iron [Fe(HQ)(3)] were included, 7 alpha/7 beta-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 5 alpha-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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