Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo
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 ruth...
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MDPI AG
2020-10-01
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| Online Access: | https://www.mdpi.com/1420-3049/25/20/4699 |
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| author | Maja Savic Aleksandar Arsenijevic Jelena Milovanovic Bojana Stojanovic Vesna Stankovic Ana Rilak Simovic Dejan Lazic Nebojsa Arsenijevic Marija Milovanovic |
| author_facet | Maja Savic Aleksandar Arsenijevic Jelena Milovanovic Bojana Stojanovic Vesna Stankovic Ana Rilak Simovic Dejan Lazic Nebojsa Arsenijevic Marija Milovanovic |
| author_sort | Maja Savic |
| collection | DOAJ |
| description | 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, <b>Ru-1</b>) and [Ru(Cl-tpy)(dach)Cl][Cl] (dach = 1,2-diaminocyclohexane, <b>Ru-2</b>) 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 IC<sub>50</sub> 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, <b>Ru-1</b> significantly reduced the growth of primary heterotopic tumor in mice, similarly to oxaliplatin. Renal damage in <b>Ru-1</b> treated mice was lower in comparison with oxaliplatin treated mice, as evaluated by serum levels of urea and creatinine and histological evaluation, but <b>Ru-1</b> 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 (<sup>1</sup>H NMR) spectroscopy. All reactions led to the formation of monofunctional thiolate adducts [Ru(Cl-tpy)(en)GS-<i>S</i>] (<b>3</b>) and [Ru(Cl-tpy)(dach)GS-<i>S</i>] (<b>4</b>). 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. |
| first_indexed | 2024-03-10T15:37:40Z |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T15:37:40Z |
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| spelling | doaj.art-94d587e528094ad59355d7ec44f2ca592023-11-20T17:04:40ZengMDPI AGMolecules1420-30492020-10-012520469910.3390/molecules25204699Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In VivoMaja Savic0Aleksandar Arsenijevic1Jelena Milovanovic2Bojana Stojanovic3Vesna Stankovic4Ana Rilak Simovic5Dejan Lazic6Nebojsa Arsenijevic7Marija Milovanovic8Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, SerbiaCenter for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, SerbiaCenter for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, SerbiaCenter for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, SerbiaDepartment of Pathology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, SerbiaDepartment of Natural Sciences, Institute for Information Technologies Kragujevac, University of Kragujevac, Jovana Cvijića bb, 34000 Kragujevac, SerbiaDepartment of Surgery, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovića 69, 34000 Kragujevac, SerbiaCenter for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, SerbiaCenter for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, SerbiaRuthenium 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, <b>Ru-1</b>) and [Ru(Cl-tpy)(dach)Cl][Cl] (dach = 1,2-diaminocyclohexane, <b>Ru-2</b>) 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 IC<sub>50</sub> 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, <b>Ru-1</b> significantly reduced the growth of primary heterotopic tumor in mice, similarly to oxaliplatin. Renal damage in <b>Ru-1</b> treated mice was lower in comparison with oxaliplatin treated mice, as evaluated by serum levels of urea and creatinine and histological evaluation, but <b>Ru-1</b> 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 (<sup>1</sup>H NMR) spectroscopy. All reactions led to the formation of monofunctional thiolate adducts [Ru(Cl-tpy)(en)GS-<i>S</i>] (<b>3</b>) and [Ru(Cl-tpy)(dach)GS-<i>S</i>] (<b>4</b>). 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.https://www.mdpi.com/1420-3049/25/20/4699colon carcinomacytotoxicityruthenium(II) complexesoxaliplatin |
| spellingShingle | Maja Savic Aleksandar Arsenijevic Jelena Milovanovic Bojana Stojanovic Vesna Stankovic Ana Rilak Simovic Dejan Lazic Nebojsa Arsenijevic Marija Milovanovic Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo Molecules colon carcinoma cytotoxicity ruthenium(II) complexes oxaliplatin |
| title | Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo |
| title_full | Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo |
| title_fullStr | Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo |
| title_full_unstemmed | Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo |
| title_short | Antitumor Activity of Ruthenium(II) Terpyridine Complexes towards Colon Cancer Cells In Vitro and In Vivo |
| title_sort | antitumor activity of ruthenium ii terpyridine complexes towards colon cancer cells in vitro and in vivo |
| topic | colon carcinoma cytotoxicity ruthenium(II) complexes oxaliplatin |
| url | https://www.mdpi.com/1420-3049/25/20/4699 |
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