Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo

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.

Synthesis, Biomacromolecular Interactions, Photodynamic NO Releasing and Cellular Imaging of Two [RuCl(qn)(Lbpy)(NO)]X Complexes

“…A series of ruthenium complexes containing the different ligands against cancer cells have been reported, these complexes could be used to reduce tumor growth, and some complexes could increase mean survival time with a relatively low cytotoxicity and genotoxicity in non-tumor cells [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. The studies on the Ru complexes with multi-mixed ligands provide a strategy to search for effective leading compound and shed light on the mechanism of action.…”

Ruthenium Complexes: An Alternative to Platinum Drugs in Colorectal Cancer Treatment

“…Ru offers octahedral coordination geometry instead of square-planar geometry of Pt(II) complexes which provide a different mode of action and reactivity than CIS [ 61 ]. Furthermore, compared to typical Pt-based drugs, many Ru-based compounds have better water solubility in the biological environment, resulting in improved effectiveness against Pt-drug resistant tumor cells [ 62 ]. This increase in water solubility may aid in balancing the hydrophilicity and hydrophobicity of Ru-complexes, resulting in increased absorption in cancer cells [ 63 , 64 ].…”

“…Administering [Ru(Cl-terpyridine)(ethylenediamine)Cl][Cl] ( 18a ) and [Ru(Cl-terpyridine)(1,2-diaminocyclohexane)Cl][Cl] ( 18b ) at 2 mg/kg dose concentration in BALB/c mice bearing CT26 mouse colon carcinoma exhibited moderate histological changes in kidney, lung, and liver but no significant changes were found in heart architecture. However, there was a lack of changes in serum creatinine, urea, AST, and ALT level [ 62 ]. Furthermore, Ru-based drugs 12a damaged kidneys by altering the glomeruli structure [ 216 , 217 ] and 8b showed toxicity in bone marrow besides kidney [ 62 ].…”

“…However, there was a lack of changes in serum creatinine, urea, AST, and ALT level [ 62 ]. Furthermore, Ru-based drugs 12a damaged kidneys by altering the glomeruli structure [ 216 , 217 ] and 8b showed toxicity in bone marrow besides kidney [ 62 ].…”

Data_Sheet_1.pdf

“…In addition, prior to determining the anti-CRC activity of the candidates in the CT 26 allograft model of CRC (a widely used animal model for cancer drug development that allows for quick and costeffective experimental testing of potential drugs), the antiproliferative activity of the CFSs of 21 candidates was examined against CT 26 cells in vitro. Previous reports have shown that the level of anti-proliferative activity differs depending on the cell line (Savic et al, 2020;Shin et al, 2021); thus, some of the CFSs exerted no or little anti-proliferative activity against CT 26 cells. Of the 21 candidates, the CFS of GM07 exerted the highest anti-proliferative effect against CT 26 cells; hence, GM07 was chosen for further investigation and the generative gut microbe was identified as O. splanchnicus through phylogenetic analysis.…”