Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI.
Photochem Photobiol. 2021 Jul;97(4):653-663. doi: 10.1111/php.13373. Epub 2021 Jan 19.
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.
这篇综述重点关注一氧化氮（NO）拮抗抗肿瘤光动力疗法（PDT）的能力。NO 的抗 PDT 作用是最近才被认识到的，需要更好地了解其机制，以便开发提高 PDT 疗效的新策略。许多 PDT 敏化剂（PS）是两亲性的，往往定位于肿瘤细胞的膜隔室中。这些隔室中的不饱和脂质在 PS 光激活后会发生过氧化降解。本文讨论了初级Ⅰ型（自由基）与Ⅱ型（单线态氧）脂质过氧化的光化学，以及与光无关的初级脂质氢过氧化物向自由基的转化。后者介导的链脂质过氧化会加剧 PDT 挑战后的膜损伤和细胞毒性。我们的研究表明，化学供体产生的 NO 可以通过拦截脂质衍生的自由基中间体来抑制链过氧化，从而保护癌细胞免受光杀伤。最近的证据表明，几种癌细胞类型在光动力挑战后会显著上调诱导型一氧化氮合酶（iNOS），而 iNOS 衍生的 NO 会增强存活细胞的耐药性以及生长和迁移侵袭性。本文讨论了 NO 和其他可能的基于 NO 的耐药机制的链断裂作用，以及克服这些负面影响的新的药物治疗方法。
