Abstract
Ruthenium complexes have attracted considerable interest as potential antitumor agents. Therefore, antitumor activity and systemic toxicity of ruthenium(II) terpyridine complexes were evaluated in heterotopic mouse colon carcinoma. In the present study, cytotoxic effects of recently synthesized ruthenium(II) terpyridine complexes [Ru(Cl-tpy)(en)Cl][Cl] (en = ethylenediamine, tpy = terpyridine, Ru-1) and [Ru(Cl-tpy)(dach)Cl][Cl] (dach = 1,2-diaminocyclohexane, Ru-2) towards human and murine colon carcinoma cells were tested in vitro and in vivo and compared with oxaliplatin, the most commonly used chemotherapeutic agent against colorectal carcinoma. Ruthenium(II) complexes showed moderate cytotoxicity with IC50 values ranging between 19.1 to 167.3 μM against two human, HCT116 and SW480, and one mouse colon carcinoma cell line, CT26. Both ruthenium(II) terpyridine complexes exerted a moderate apoptotic effect in colon carcinoma cells, but induced significant necrotic death. Additionally, both complexes induced cell cycle disturbances, but these effects were specific for the cell line. Further, Ru-1 significantly reduced the growth of primary heterotopic tumor in mice, similarly to oxaliplatin. Renal damage in Ru-1 treated mice was lower in comparison with oxaliplatin treated mice, as evaluated by serum levels of urea and creatinine and histological evaluation, but Ru-1 induced higher liver damage than oxaliplatin, evaluated by the serum levels of alanine aminotransferase. Additionally, the interaction of these ruthenium(II) terpyridine complexes with the tripeptide glutathione (GSH) was investigated by proton nuclear magnetic resonance (1H NMR) spectroscopy. All reactions led to the formation of monofunctional thiolate adducts [Ru(Cl-tpy)(en)GS-S] (3) and [Ru(Cl-tpy)(dach)GS-S] (4). Our data highlight the significant cytotoxic activity of [Ru(Cl-tpy)(en)Cl][Cl] against human and mouse colon carcinoma cells, as well as in vivo antitumor activity in CT26 tumor-bearing mice similar to standard chemotherapeutic oxaliplatin, accompanied with lower nephrotoxicity in comparison with oxaliplatin.
Highlights
Platinum-based drugs such as cisplatin, carboplatin, and oxaliplatin have been among the most effective chemotherapeutic agents in carcinoma treatment for years
Investigated ruthenium complexes, KP1019 and its sodium salt analogue KP1339, which are active against colon carcinomas, were thought to exhibit tumor selectivity via HSA (Human Serum Albumin) mediated pathways based on increased permeability and the retention effect of tumor tissues
The results revealed that the level of Lactate Dehydrogenase (LDH) release was higher from CT26 cells treated with ruthenium(II) terpyridine complexes for 24 h compared to the cells treated with oxaliplatin, indicating that ruthenium(II) terpyridine complexes could affect the cell membrane integrity (Figure 5)
Summary
Platinum-based drugs such as cisplatin, carboplatin, and oxaliplatin have been among the most effective chemotherapeutic agents in carcinoma treatment for years. Investigated ruthenium complexes, KP1019 and its sodium salt analogue KP1339, which are active against colon carcinomas, were thought to exhibit tumor selectivity via HSA (Human Serum Albumin) mediated pathways based on increased permeability and the retention effect of tumor tissues. This effect was attributed to the altered structure of tumor blood vessels that allows macromolecules, such as a drug-HSA complex, to pass through gaps in endothelial cells of blood vessels and accumulate in tumor tissue [9].
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