Antagonistic effect of a nitric oxide donor agents based on ruthenium complex combined with cisplatin on lung tumor cell lines

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)2(NO2)(solv)]PF6 and cis-Ru(bpy)2(NO)(pic)](PF6)3, 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)2(NO)(pic)](PF6)3 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.