Nitric Oxide-elicited Resistance to Antitumor Photodynamic Therapy via Inhibition of Membrane Free Radical-mediated Lipid Peroxidation

Abstract

This review focuses on the ability of nitric oxide (NO) to antagonize antitumor photodynamic therapy (PDT). NO's anti-PDT effects were recognized relatively recently and require a better mechanistic understanding for developing new strategies to improve PDT efficacy. Many PDT sensitizers (PSs) are amphiphilic and tend to localize in membrane compartments of tumor cells. Unsaturated lipids in these compartments can undergo peroxidative degradation after PS photoactivation. Primary Type I (free radical) vs. Type II (singlet oxygen) photochemistry of lipid peroxidation is discussed, along with light-independent turnover of primary lipid hydroperoxides to free radical species. Chain lipid peroxidation mediated by the latter exacerbates membrane damage and cytotoxicity after a PDT challenge. Our studies have shown that NO from chemical donors can suppress chain peroxidation by intercepting lipid-derived free radical intermediates, thereby protecting cancer cells against photokilling. More recent evidence has revealed that inducible NO synthase (iNOS) is dramatically upregulated in several cancer cell types after a photodynamic challenge, and that iNOS-derived NO enhances resistance as well as growth and migratory aggressiveness of surviving cells. Chain breaking by NO and other possible NO-based resistance mechanisms are discussed, along with novel pharmacologic approaches for overcoming these negative effects.