👤 de Carvalho NC

Herein, ruthenium complexes containing heterocyclic thioamidates [Ru(mmi)(bipy)(dppb)]PF₆ (1), [Ru(tzdt)(bipy)(dppb)]PF₆ (2), [Ru(dmp)(bipy)(dppb)]PF₆ (3) and [Ru(mpca)(bipy)(dppb)]PF₆ (4) were investigated for their cellular and molecular effects in cancer cell lines. Complexes 1 and 2 were the most potent of the four compounds against a panel of different cancer cell lines in monolayer cultures and showed potent cytotoxicity in a 3D model of multicellular spheroids that formed from human hepatocellular carcinoma HepG2 cells. In addition, both complexes were able to bind to DNA in a calf thymus DNA model. Compared to the controls, a reduction in cell proliferation, phosphatidylserine externalization, internucleosomal DNA fragmentation, and the loss of the mitochondrial transmembrane potential were observed in HepG2 cells that were treated with these complexes. Additionally, coincubation with a pan-caspase inhibitor (Z-VAD(OMe)-FMK) reduced the levels of apoptosis that were induced by these compounds compared to those in the negative controls, indicating that cell death through apoptosis occurred via a caspase-dependent pathway. Moreover, these complexes also induced the phosphorylation of ERK1/2, and coincubation with an MEK inhibitor (U0126), which is known to inhibit the activation of ERK1/2, but not JNK/SAPK and p38 MAPK inhibitors, reduced the complexes-induced apoptosis compared to that in the negative controls, indicating that the induction of apoptotic cell death occurred through ERK1/2 signaling in HepG2 cells. On the other hand, no increase in oxidative stress was observed in HepG2 cells treated with the complexes, and the complexes-induced apoptosis was not reduced with coincubation with the antioxidant N-acetylcysteine or a p53 inhibitor compared to that in the negative controls, indicating that apoptosis occurred via oxidative stress- and p53-independent pathways. Finally, these complexes also reduced the growth of HepG2 cells that were engrafted in C.B-17 SCID mice compared to that in the negative controls. These results indicated that these complexes are novel anticancer drug candidates for liver cancer treatment. Show less

Ruthenium-based compounds have gained great interest due to their potent cytotoxicity in cancer cells; however, much of their potential applications remain unexplored. In this paper, we report the synthesis of a novel ruthenium complex with xanthoxylin (RCX) and the investigation of its cellular and molecular action in human hepatocellular carcinoma HepG2 cells. We found that RCX exhibited a potent cytotoxic effect in a panel of cancer cell lines in monolayer cultures and in a 3D model of multicellular cancer spheroids formed from HepG2 cells. This compound is detected at a high concentration in the cell nuclei, induces DNA intercalation and inhibits DNA synthesis, arresting the cell cycle in the S-phase, which is followed by the activation of the caspase-mediated apoptosis pathway in HepG2 cells. Gene expression analysis revealed changes in the expression of genes related to cell cycle control, apoptosis and the MAPK pathway. In addition, RCX induced the phosphorylation of ERK1/2, and pretreatment with U-0126, an MEK inhibitor known to inhibit the activation of ERK1/2, prevented RCX-induced apoptosis. In contrast, pretreatment with a p53 inhibitor (cyclic pifithrin-α) did not prevent RCX-induced apoptosis, indicating the activation of a p53-independent apoptosis pathway. RCX also presented a potent in vivo antitumor effect in C.B-17 SCID mice engrafted with HepG2 cells. Altogether, these results indicate that RCX is a novel anticancer drug candidate. Show less

A series of benzothiazole-substituted trisbipyridine ruthenium(II) analogues {[Ru(bpy)(2)(4,5'-bbtb)](2+), [Ru(bpy)(2)(5,5'-bbtb)](2+) and [Ru(bpy)(2)(5-mbtb)](2+) [bpy is 2,2'-bipyridine, bbtb is bis(benzothiazol-2-yl)-2,2'-bipyridine, 5-mbtb is 5-(benzothiazol-2-yl),5'-methyl-2,2'-bipyridine]} have been prepared and compared with the complex [Ru(bpy)(2)(4,4'-bbtb)](2+) reported previously. From the UV-vis spectral studies, substitution at the 5-position of the bpy causes the ligand-centred transitions to occur at considerably lower energy than for those with the functionality at the 4-position, while at the same time causing the emission to be effectively quenched. However, substitution at the 4-position causes the metal-to-ligand charge transfer to occur at lower energies. Fluorescent intercalator displacement studies indicate that the doubly substituted complexes displace ethidium bromide from a range of oligonucleotides, with the greater preference shown for bulge and hairpin sequences by the Lambda enantiomer. Since the complexes only show small variation in the UV-vis spectra on the introduction of calf thymus DNA and a small increase in fluorescence they do not appear to be intercalators, but appear to associate within one of the grooves. All of the reported bisbenzothiazole complexes show reasonable cytotoxicity against a range of human cancer cell lines. Show less