Myśliwiec Angelika, Bartusik-Aebisher Dorota, Aebisher David
Department of Biochemistry and General Chemistry, Medical Faculty, Collegium Medicum, University of Rzeszów, 35-959 Rzeszów, Poland.
Department of Photomedicine and Physical Chemistry, Medical Faculty, Collegium Medicum, University of Rzeszów, 35-959 Rzeszów, Poland.
Molecules. 2025 Jun 29;30(13):2802. doi: 10.3390/molecules30132802.
Nitric oxide (NO), the first gaseous molecule identified as a signaling mediator, plays a pivotal role in numerous physiological processes including cardiovascular regulation, immune response, and neurotransmission. Synthesized from L-arginine by nitric oxide synthase (NOS), NO exerts both protective and cytotoxic effects depending on its local concentration. At low levels, NO supports tumor growth by mitigating oxidative stress, while at high concentrations, it induces apoptosis through mechanisms such as p53 activation, cytochrome c release, and peroxynitrite formation. These dual properties position NO as a complex but promising agent in cancer therapy. Recent studies have highlighted the potential of NO in enhancing the efficacy of photodynamic therapy (PDT), where it synergizes with reactive oxygen species (ROS) to induce cytotoxic effects in tumor cells. Despite its promise, challenges such as rapid diffusion and limited tumor accumulation hinder NO's therapeutic utility. This has spurred the development of NO donors and nanotechnology-based delivery systems to enable controlled, site-specific release. Moreover, NO has been shown to counteract multidrug resistance, improve tumor perfusion by dilating vasculature, and potentiate ROS-based therapies like PDT and radiotherapy. However, an emerging concern is NO's role in promoting proliferation and migration of non-targeted "bystander" tumor cells following PDT-induced stress, primarily through iNOS upregulation. This feedback loop can contribute to tumor aggressiveness and metastasis, underscoring the need for a deeper understanding of NO's molecular actions. While iNOS inhibitors show preclinical promise in various inflammatory and neoplastic conditions, no such agents have reached clinical approval, due to the complexity and context-dependent effects of NO. Future research should focus on refining NO delivery systems, developing selective iNOS inhibitors, and elucidating NO's dual role in cancer biology to fully harness its therapeutic potential in PDT and beyond.
一氧化氮（NO）是首个被确定为信号传导介质的气体分子，在包括心血管调节、免疫反应和神经传递在内的众多生理过程中发挥着关键作用。NO由一氧化氮合酶（NOS）从L-精氨酸合成，根据其局部浓度发挥保护和细胞毒性作用。在低水平时，NO通过减轻氧化应激来支持肿瘤生长，而在高浓度时，它通过p53激活、细胞色素c释放和过氧亚硝酸盐形成等机制诱导细胞凋亡。这些双重特性使NO成为癌症治疗中一种复杂但有前景的药物。最近的研究强调了NO在增强光动力疗法（PDT）疗效方面的潜力，在该疗法中它与活性氧（ROS）协同作用，在肿瘤细胞中诱导细胞毒性作用。尽管前景广阔，但诸如快速扩散和肿瘤蓄积有限等挑战阻碍了NO的治疗效用。这促使了NO供体和基于纳米技术的递送系统的开发，以实现可控的、位点特异性释放。此外，NO已被证明可对抗多药耐药性，通过扩张血管改善肿瘤灌注，并增强基于ROS的疗法，如PDT和放射疗法。然而，一个新出现的问题是，PDT诱导应激后，NO在促进非靶向“旁观者”肿瘤细胞的增殖和迁移方面所起的作用，主要是通过诱导型一氧化氮合酶（iNOS）的上调。这种反馈回路可导致肿瘤侵袭性和转移，凸显了深入了解NO分子作用的必要性。虽然iNOS抑制剂在各种炎症和肿瘤性疾病的临床前研究中显示出前景，但由于NO的复杂性和依赖于背景的效应，尚无此类药物获得临床批准。未来的研究应专注于优化NO递送系统、开发选择性iNOS抑制剂，以及阐明NO在癌症生物学中的双重作用，以充分发挥其在PDT及其他方面的治疗潜力。
