A ruthenium-based 5-fluorouracil complex with enhanced cytotoxicity and apoptosis induction action in HCT116 cells

Abstract

Combination of multifunctionalities into one compound is a rational strategy in medicinal chemical design, and have often been used with metallodrug-based compounds. In the present study, we synthesized a novel ruthenium-based 5-fluorouracil complex [Ru(5-FU)(PPh3)2(bipy)]PF6 (PPh3 = triphenylphosphine; and bipy = 2,2′-bipyridine) with enhanced cytotoxicity in different cancer cells, and assessed its apoptosis induction action in human colon carcinoma HCT116 cells. The complex was characterized by infrared, cyclic voltammetry, molar conductance measurements, elemental analysis, NMR experiments and X-ray crystallographic analysis. In both 2D and 3D cell culture models, the complex presented cytotoxicity to cancer cells more potent than 5-FU. A typical morphology of apoptotic cell death, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HCT116 cells. Moreover, the pre-treatment with Z-DEVD-FMK, a caspase-3 inhibitor, reduced the apoptosis induced by the complex, indicating cell death by apoptosis through caspase-dependent and mitochondrial intrinsic pathways. The complex failed to induce reactive oxygen species production and DNA intercalation. In conclusion, the novel complex displays enhanced cytotoxicity to different cancer cells, and is able to induce caspase-mediated apoptosis in HCT116 cells.

A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells

“…The design of metallodrug-based compounds is an interesting strategy in medicinal chemistry [24] , [25] , [26] , [27] , [28] , [29] , [30] . The most important metallodrug-based compounds are the platinum-based antineoplastic agents.…”

Ru(II)-Thymine Complex Causes Cell Growth Inhibition and Induction of Caspase-Mediated Apoptosis in Human Promyelocytic Leukemia HL-60 Cells

“…Other ruthenium complexes have been previously reported as potent cytotoxic agents, including cyclometalated ruthenium β-carboline complexes, which were cytotoxic to lung, liver, breast, and cervical cancers [ 8 ]; piplartine-containing ruthenium complexes, which were cytotoxic to colon, tongue, liver, breast, skin, and hematological cancers [ 5 ]; a ruthenium complex with xanthoxylin, which was cytotoxic to colon, breast, liver, tongue, gastric, skin, and hematological cancers [ 9 ]; ruthenium imidazole complexes, which were cytotoxic to lung, liver, breast, and cervical cancers [ 19 ]; and, a ruthenium-based 5-fluorouracil complex, which had enhanced cytotoxicity to breast, colon, liver, tongue, skin, and hematological cancers [ 10 ]. The IC 50 values of these compounds are below 10 μM for most of the tested cancer cell lines.…”

“…Ruthenium polypyridyl complexes induce apoptosis in BEL-7402 cells through a ROS-mediated mitochondrial dysfunction pathway [ 24 ]. Moreover, the ruthenium-based 5-fluorouracil complex induces caspase-mediated apoptosis in HCT116 cells [ 10 ]. Herein, we observed that the Ru(II)-thymine complex induces caspase-mediated apoptosis in HL-60 cells.…”

“…Therefore, many ruthenium complexes have been designed and synthesized with several ligands, resulting in metallodrugs with action in cancer cells of different histological types. Interestingly, this feature is strictly dependent on the nature of the ligands, and the complexes can act via diverse mechanisms, including induction of reactive oxygen species (ROS), binding of DNA, and cell death via apoptosis pathways [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. In particular, NAMI-A ([ImH][trans-RuCl 4 (DMSO)(Im)], where Im = imidazole and DMSO = dimethylsulfoxide) and KP1019 ([IndH][trans-RuCl 4 (Ind) 2 ], where Ind = indazole) are currently in phase I/II clinical trials, with promising results [ 11 , 12 ].…”

Antitumor Effect of the Essential Oil from the Leaves of Croton matourensis Aubl. (Euphorbiaceae)

“…Cell viability was measured by the Alamar blue assay and was performed as previously described [ 34 , 35 , 36 ]. For all experiments, cells were plated in 96-well plates.…”