Graminha Angelica E, Becceneri Amanda B, Rios Rafaella R, Cominetti Márcia Regina, Biazzotto Juliana Cristina, Santana da Silva Roberto
Laboratory of Photochemistry and Bioinorganic Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo (USP), Av. Do Café, Vila Monte Alegre, Ribeirão Preto, São Paulo, 14040-903, Brazil; Institute of Chemistry, São Paulo State University, Av. Prof. Francisco Degni, 55, 14800-900, Araraquara, São Paulo, Brazil.
Laboratory of Photochemistry and Bioinorganic Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo (USP), Av. Do Café, Vila Monte Alegre, Ribeirão Preto, São Paulo, 14040-903, Brazil.
Nitric Oxide. 2025 Oct;158:52-61. doi: 10.1016/j.niox.2025.05.009. Epub 2025 May 31.
Nitric oxide (NO) is a versatile biological messenger involved in numerous physiological processes and anticancer mechanisms. Its functions are highly dependent on its concentration and the specific site of action. In this study, we investigated the effects of controlled NO release mediated by ruthenium-based compounds. The tests demonstrated the significant potential of combining cisplatin with the non-cytotoxic ruthenium nitrosyl complexes cis-[Ru(bpy)(NO)(solv)]PF and cis-Ru(bpy)(NO)(pic)](PF), where bpy = 2,2'-bipyridine ,pic = 4-picoline and solv = solvent. This combination increased selectivity between non-tumoral and tumoral lung cells (MRC-5/A549) compared to the selectivity index of cisplatin alone. These nitrosyl complexes exhibited an antagonistic interaction with cisplatin, reducing its cytotoxic efficacy. Cell cycle and apoptosis assays revealed that the cisplatin/Ru combination more effectively inhibited cisplatin's cytotoxic effect on the MRC-5 non-tumoral lung cell line compared to the A549 tumoral cell line. Morphological assays conducted in 3D culture with the cis-Ru(bpy)(NO)(pic) complex confirmed its chemopreventive behavior, as the 3D system closely mimics in vivo conditions. Moreover, the absence of cytotoxicity in these ruthenium nitrosyl complexes highlights their potential as promising candidates for adjuvant therapy in combination with other drugs.
一氧化氮（NO）是一种多功能生物信使，参与众多生理过程和抗癌机制。其功能高度依赖于其浓度和特定作用位点。在本研究中，我们研究了钌基化合物介导的可控NO释放的影响。测试证明了顺铂与非细胞毒性的亚硝酰钌配合物顺式-[Ru(bpy)(NO)(solv)]PF和顺式-Ru(bpy)(NO)(pic)](PF)联合使用的巨大潜力，其中bpy = 2,2'-联吡啶，pic = 4-甲基吡啶，solv = 溶剂。与单独使用顺铂的选择性指数相比，这种联合提高了非肿瘤性和肿瘤性肺细胞（MRC-5/A549）之间的选择性。这些亚硝酰配合物与顺铂表现出拮抗相互作用，降低了其细胞毒性功效。细胞周期和凋亡分析表明，与A549肿瘤细胞系相比，顺铂/Ru组合更有效地抑制了顺铂对MRC-5非肿瘤性肺细胞系的细胞毒性作用。用顺式-Ru(bpy)(NO)(pic)配合物在3D培养中进行的形态学分析证实了其化学预防行为，因为3D系统紧密模拟体内条件。此外，这些亚硝酰钌配合物无细胞毒性，突出了它们作为与其他药物联合辅助治疗的有前景候选物的潜力。
