Redox and apoptotic potential of novel ruthenium complexes in rat blood and heart

Abstract

Ruthenium(II) complexes offer the potential for lower toxicity compared to platinum(II) complexes. Our study aimed to compare cardiotoxicity of [Ru(Cl-tpy)(en)Cl][Cl], [Ru(Cl-tpy)(dach)Cl][Cl], [Ru(Cl-tpy)(bpy)Cl][Cl], cisplatin and saline through assessment of redox status and relative expression of apoptosis-related genes. A total of 40 Wistar albino rats were divided into five groups. Ruthenium groups received intraperitoneally single dose of complexes (4 mg/kg/week) for 4-weeks period; cisplatin group received cisplatin (4 mg/kg/week) and control group received saline (4 mL/kg/week) in the same manner as ruthenium groups. In collected blood and heart tissue samples, spectrophotometrically determination of oxidative stress biomarkers was performed. The relative expression of apoptosis-related genes (Bcl-2, Bax, and caspase-3) in hearts was examined by RT-PCR. Our results showed that systemic and cardiac pro-oxidative markers (TBARS and NO2-) were significantly lower in ruthenium groups compared to cisplatin group, while concentrations of antioxidative parameters (CAT, SOD, and GSSG) were significantly higher. Ruthenium administration led to significantly lower gene expression of Bax and caspase-3 compared to cisplatin-treated rats, while Bcl-2 remained unchanged. Applied ruthenium complexes have less pronounced potential for induction of oxidative stress-mediated cardiotoxicity compared to cisplatin. These findings may help for future studies that should clarify the mechanisms of cardiotoxicity of ruthenium-based metallodrugs.

Ruthenium Half-Sandwich Type Complexes with Bidentate Monosaccharide Ligands Show Antineoplastic Activity in Ovarian Cancer Cell Models through Reactive Oxygen Species Production

“…Currently available ruthenium complexes with antineoplastic activity have diverse modes of action involving (mitochondrial) reactive oxygen species production [ 9 , 15 , 41 , 42 ] and the induction of DNA damage [ 43 , 44 ]. We detected an increase in the expression of an oxidative stress marker, 4-hydroxy-nonenal (4HNE), at the level of the whole lane, as well as when a specific band was assessed, in A2780 cells treated with the active ruthenium complexes Ru-2a , Ru-4 , Ru-6 , and Ru-8 corresponding to the IC 50 values ( Figure 8 ).…”

“…Apparently, the mode of action of ruthenium complexes is pleiotropic and involves binding to polynucleotides [ 44 ] or the production of reactive oxygen species [ 9 , 15 , 41 , 42 ]. The actual mode of action or the dominant pathway to induce cytostasis differs for different classes of ruthenium complexes [ 15 ].…”

“…The functional role of reactive oxygen species production was confirmed by the application of GSH and NAC, two strong reductants, that reverted the cytostatic effects of the bioactive ruthenium complexes, as well as confirmed by using vitamin E. The source of reactive oxygen species was other than the mitochondria. Reactive oxygen species production was shown to be cytostatic in numerous carcinomas [ 9 , 15 , 41 , 42 , 57 ]. In addition to oxidative stress, we showed that the effects of ruthenium complexes is potentiated by a PARP inhibitor, rucaparib, similar to others [ 41 , 42 , 49 , 50 ].…”

“…For example, Ru-based drugs have improved cellular entry under hypoxic conditions that characterize aggressively growing tumors [ 7 , 8 ], or they can be delivered by binding to transferrin [ 6 ]. Importantly, multiple studies have pointed out reduced toxicity for Ru-complexes as compared to Pt complexes in both cellular and animal models [ 9 , 10 , 11 , 12 ]. Both Pt- and Ru-based drugs can be targeted to enzymes or cellular compartments by coupling bait molecules such as biotin, nonsteroidal anti-inflammatory drugs, hormones, or carbohydrates to enhance their chemotherapeutic potential (thoroughly reviewed in [ 6 ]).…”

“…Importantly, multiple studies have pointed out reduced toxicity for Ru-complexes as compared to Pt complexes in both cellular and animal models [9][10][11][12]. Both Pt-and Ru-based drugs can be targeted to enzymes or cellular compartments by coupling bait molecules such as biotin, nonsteroidal anti-inflammatory drugs, hormones, or carbohydrates to enhance their chemotherapeutic potential (thoroughly reviewed in [6]).…”