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.

Wider indications and more efficient drug delivery: A bibliometric analysis and visualization of photodynamic therapy in skin cancer

“…So far, our understanding of the mechanism of PDT in treating cancer, not only skin cancer, is incomprehensive and incomplete. In our perspective, there are two urgent problems to be addressed that one is "which pathway or molecule is related to the 41 The antitumor effectiveness of PDT can be further improved by finding and removing causes of PDT resistance.…”

Increased PDT Efficacy When Associated with Nitroglycerin: A Study on Retinoblastoma Xenografted on Mice

“…Some studies showed that a red laser is able to release NO storage from tissue [48,49]. Lohr et al showed in both purified systems and the myocardium that R/NIR light can decay nitrosyl hemes and release NO, and that this released NO may enhance the cardioprotective effects of nitrite.…”

Recent Photosensitizer Developments, Delivery Strategies and Combination‐based Approaches for Photodynamic Therapy†

“…It should be noted that regarding the NOS activity, scarce studies so far have been reported that explore the possibility of the combination of both the inhibition of NOS, and PDT may potentiate the performance of the photosensitizers (241). Nevertheless, enough evidence has been reported in the literature that these inhibitors might have the potential to be used alone or in combination with other existing therapies such as radiotherapy as well as chemotherapy to explore the possibility of synergistic effects (229,242).…”