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Antagonistic effect of a nitric oxide donor agents based on ruthenium complex combined with cisplatin on lung tumor
Angelica E Graminha1, Amanda B Becceneri2, Rafaella R Rios2
1Laboratory 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.
Abstract:
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.
Insights
Ruthenium nitrosyl complexes combined with cisplatin show enhanced selectivity for lung cancer cells. These non-cytotoxic ruthenium compounds may serve as adjuvant therapy, reducing side effects on healthy cells.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Inorganic Chemistry
Background:
- Nitric oxide (NO) is a crucial biological messenger with diverse roles in physiology and cancer.
- The efficacy of NO-based therapies depends on precise control over its concentration and delivery.
- Ruthenium-based compounds offer potential for controlled nitric oxide release.
Purpose of the Study:
- To investigate the effects of controlled nitric oxide release from ruthenium nitrosyl complexes.
- To evaluate the combination of cisplatin with ruthenium nitrosyl complexes for cancer therapy.
- To assess the selectivity and efficacy of these combinations against lung cancer cells.
Main Methods:
- Synthesis and characterization of ruthenium nitrosyl complexes.
- In vitro studies using human lung cell lines (MRC-5 and A549).
- Cell cycle analysis, apoptosis assays, and 3D cell culture models.
Main Results:
- Ruthenium nitrosyl complexes combined with cisplatin demonstrated increased selectivity towards tumoral lung cells (A549) over non-tumoral cells (MRC-5).
- An antagonistic interaction was observed, where ruthenium complexes reduced cisplatin's cytotoxic effect on healthy cells.
- 3D culture models confirmed the chemopreventive behavior of cis-[Ru(bpy)2(NO)(pic)](PF6)3.
Conclusions:
- Ruthenium nitrosyl complexes can be effectively combined with cisplatin to improve cancer treatment selectivity.
- These non-cytotoxic ruthenium complexes show promise as adjuvant agents in cancer therapy.
- Controlled NO release from ruthenium complexes offers a strategy to mitigate chemotherapy side effects.
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