Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia.
Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia.
Molecules. 2020 Oct 14;25(20):4699. doi: 10.3390/molecules25204699.
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, ) and [Ru(Cl-tpy)(dach)Cl][Cl] (dach = 1,2-diaminocyclohexane, ) 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 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, significantly reduced the growth of primary heterotopic tumor in mice, similarly to oxaliplatin. Renal damage in treated mice was lower in comparison with oxaliplatin treated mice, as evaluated by serum levels of urea and creatinine and histological evaluation, but 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 (H NMR) spectroscopy. All reactions led to the formation of monofunctional thiolate adducts [Ru(Cl-tpy)(en)GS-] () and [Ru(Cl-tpy)(dach)GS-] (). 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.
钌配合物作为潜在的抗肿瘤药物引起了人们的极大兴趣。因此，我们评估了钌（II）三联吡啶配合物的抗肿瘤活性和全身毒性。在本研究中，我们在异质小鼠结肠癌中测试了最近合成的钌（II）三联吡啶配合物[Ru(Cl-tpy)(en)Cl][Cl]（en = 乙二胺，tpy = 三联吡啶）和[Ru(Cl-tpy)(dach)Cl][Cl]（dach = 1,2-二氨基环己烷）对人结肠癌和鼠结肠癌细胞的体外和体内的细胞毒性作用，并与奥沙利铂（oxaliplatin）进行了比较，奥沙利铂是治疗结直肠癌最常用的化疗药物。钌（II）配合物对两种人结肠癌细胞系 HCT116 和 SW480 以及一种鼠结肠癌细胞系 CT26 的 IC 值范围在 19.1 至 167.3 μM 之间，表现出中等的细胞毒性。两种钌（II）三联吡啶配合物在结肠癌细胞中均产生适度的凋亡作用，但诱导明显的坏死性死亡。此外，两种配合物均诱导细胞周期紊乱，但这些作用是细胞系特异性的。此外，与奥沙利铂相比，能显著降低小鼠体内原发性异位肿瘤的生长。与奥沙利铂治疗的小鼠相比，用 治疗的小鼠的肾损伤较低，通过血清尿素和肌酐水平和组织学评估来评估，但比奥沙利铂诱导更高的肝损伤，通过血清丙氨酸氨基转移酶水平来评估。此外，通过质子核磁共振（H NMR）光谱研究了这些钌（II）三联吡啶配合物与三肽谷胱甘肽（GSH）的相互作用。所有反应均导致形成单功能硫醇加合物[Ru(Cl-tpy)(en)GS-]（）和[Ru(Cl-tpy)(dach)GS-]（）。我们的数据突出了[Ru(Cl-tpy)(en)Cl][Cl]对人结肠癌和鼠结肠癌细胞的显著细胞毒性活性，以及在 CT26 荷瘤小鼠中的体内抗肿瘤活性，与标准化疗药物奥沙利铂相似，与奥沙利铂相比，肾毒性较低。
