Photochemical Properties of trans-[Ru(NH3 )4 (bpa)(L)]2+ (L = py, isn, 4-acpy or 4-pic).

Photochemical reactions of ruthenium (II) complexes of type trans-[Ru(NH3 )4 LL']2+ , where L is a nitrogenous heterocyclic ligand, pyridine (py), isonicotinamide (isn), 4-acetylpyridine (4-acpy) or 4-picoline (4-pic), and L´ is a 1,2-bis(4-pyridyl)ethane (bpa) ligand, were studied with the purpose of evaluating the ligand exchange when, in solution, the complexes are irradiated at the wavelengths of 365, 436, 480 and 519 nm. The study revealed that at lower wavelengths, a labilization process is observed for py and 4-pic ligands, even at low quantum yields, indicating the dependence of the photolabeling process on the wavelength. The study also reveals that for the filters of greater wavelength, the processes of photolabilization do not occur for any of the studied complexes. The study also shows that there are no photolization processes for the complexes obtained with the isn and 4-acpy ligands, and it is therefore possible to classify them as nonreactive.

MDR1 and cytochrome P450 gene-expression profiles as markers of chemosensitivity in human chronic myelogenous leukemia cells treated with cisplatin and Ru(III) metallocomplexes.

Leukemia is a major type of cancer affecting a significant segment of the population, and especially children. In fact, leukemia is the most frequent childhood cancer, with 26 % of all cases, and 20 % mortality. The multidrug resistance phenotype (MDR) is considered one of the major causes of failure in cancer chemotherapy. The present study aimed to investigate the relationship between the expression of MDR1 and CYP450 genes in human chronic myelogenous leukemia cells (K-562) treated with cisplatin (cisPt) and two ruthenium-based coordinated complexes [cisCRu(III) and cisDRu(III)]. The tested compounds induced apoptosis in K-562 tumor cells as evidenced by caspase 3 activation. Results also revealed that the amplification of P-gp gene is greater in K-562 cells exposed to cisPt and cisCRu(III) than cisDRu(III). Taken together, all these results strongly demonstrate that MDR-1 overexpression in K-562 cells could be associated to a MDR phenotype, and moreover, it is also contributing to the platinum and structurally related compound, resistance in these cells.

Cytotoxic effects of the compound cis-tetraammine(oxalato)ruthenium(III) dithionate on K-562 human chronic myelogenous leukemia cells.

Chemotherapy is a common treatment for leukemia. Ruthenium complexes have shown potential utility in chemotherapy and photodynamic therapy. The identification of new chemotherapeutics agents is critical for further progress in the treatment of leukemia. Ruthenium complexes generally have lower toxicities compared to cisplatin attributed to their specific accumulation in cancer tissues. Based on these evidences, in the present work we studied the cytotoxic activity of the ruthenium(III) compound cis-tetraammine(oxalato)ruthenium(III) dithionate - {cis-[Ru(C2O4)(NH3)4]2(S2O6)} against human chronic myelogenous leukemia cells (K-562) tumor cell line. The tested compound induces cell death in a dose and time dependent manner on K-562 cells. It is found that the effect was improved linearly while prolonging the incubation time. Compared to the cell cycle profiles of untreated cells, flow cytometric analysis indicated the sub-G1 arresting effect of ruthenium compound on K-562 cells. In our study, {cis-[Ru(C2O4)(NH3)4]2(S2O6)} shows a significant increase in tailed cells in any of the concentrations tested compared with negative control. Consequently, the concentration of {cis-[Ru(C2O4)(NH3)4]2(S2O6)} might be associated cytotoxicity with direct effect on K-562 cells DNA. Thus, it can be deducted that ruthenium-based compounds present selectivity to enter both tumor and normal cells. Additional studies are needed to determine the molecular mechanisms of the active components and to evaluate the potential in vivo anticancer activity of the cis-tetraammine(oxalato)ruthenium(III) dithionate.

The ruthenium complexes cis-(dichloro)tetramineruthenium(III) chloride and cis-tetraammine(oxalato)ruthenium(III) dithionate overcome resistance inducing apoptosis on human lung carcinoma cells (A549).

Lung cancer is one of the leading causes of death in the world, and non-small cell lung carcinoma accounts for approximately 75-85 % of all lung cancers. In the present work, we studied the antitumor activity of the compound cis-(dichloro)tetramineruthenium(III) chloride {cis-[RuCl2(NH3)4]Cl} against human lung carcinoma tumor cell line A549. The present study aimed to investigate the relationship between the expression of MDR1 and CYP450 genes in human lung carcinoma cell lines A549 treated with cisCarboPt, cisCRu(III) and cisDRu(III). The ruthenium-based coordinated complexes presented low cytotoxic and antiproliferative activities, with high IC50 values, 196 (±15.49), 472 (±20.29) and 175 (±1.41) for cisCarboPt, cisCRu(III) and cisDRu(III), respectively. The tested compounds induced apoptosis in A549 tumor cells as evidenced by caspase 3 activation, but only at high concentrations. Results also revealed that the amplification of P-gp gene is greater in A549 cells exposed to cisCarboPt and cisCRu(III) than cisDRu(III). Taken together all these results strongly demonstrate that MDR-1 over-expression in A549 cells could be associated to a MDR phenotype of these cells and moreover, it is also contributing to the platinum, and structurally-related compound, resistance in these cells. The identification and characterization of novel mechanisms of drug resistance will enable the development of a new generation of anti-cancer drugs that increase cancer sensitivity and/or represent more effective chemotherapeutic agents.

Induction of cell cycle arrest and apoptosis by ruthenium complex cis-(dichloro)tetramineruthenium(III) chloride in human lung carcinoma cells A549.

Lung cancer is one of the leading causes of death in the world, and non-small cell lung carcinoma (NSCLC) accounts for approximately 75-85% of all lung cancers. In the present work, we studied the cytotoxic activity, cell cycle arrest and induction apoptosis of the compound cis-(dichloro)tetramineruthenium(III) chloride {cis-[RuCl(2)(NH(3))(4)]Cl} in human lung carcinoma tumor cell line A549. The results of MTT and trypan blue assays showed that cis-[RuCl(2)(NH(3))(4)]Cl causes reduction in the viability of A549 cells when treating with 95 and 383 µM of the compound for 48 and 72 h. Lower concentrations of the compound (19, 3.8 and 0.38 µM), however, only slightly affected cell viability. The IC(50) value for the compound was about 383 µM. Survival analysis of the A549 cells after treatment with ruthenium(III) compound using long term clonogenic assay showed that it reduced colony formation ability at concentrations of 0.38 and 3.8 µM, and at concentrations of 95 and 383 µM no colonies were observed. Cell cycle analysis showed that compound ruthenium led to an accumulation of A549 cells in S phase and increased in the sub-G1 peak. In addition, cis-(dichloro)tetramineruthenium(III) chloride treatment induced apoptosis, as observed by the increased numbers of annexin V-positive cells and increased messenger RNA expression of caspase-3.

The ruthenium complex cis-(dichloro)tetrammineruthenium(III) chloride induces apoptosis and damages DNA in murine sarcoma 180 cells.

Ruthenium (III) complexes are increasingly attracting the interest of researchers due to their promising pharmacological properties. Recently, we reported that the cis-(dichloro)tetrammineruthenium (III) chloride compound has cytotoxic effects on murine sarcoma 180 (S-180) cells. In an effort to understand the mechanism responsible for their cytotoxicity, study we investigated the genotoxicity, cell cycle distribution and induction of apoptosis caused by cis- (dichloro) tetrammineruthenium (III) chloride in S-180 tumour cells. cis-(dichloro) tetrammineruthenium (III) chloride treatment induced significant DNA damage in S-180 cells, as detected by the alkaline comet assay. In the cell cycle analysis, cis-(dichloro) tetrammineruthenium (III) chloride caused an increase in the number of cells in G1 phase, accompanied by a decrease in the S and G2 phases after 24 h of treatment. In contrast, the cell cycle distribution of S-180 cells treated with cis-(dichloro) tetrammineruthenium (III) chloride for 48 h showed a concentration-dependent increase in the sub-G1 phase (indicating apoptosis), with a corresponding decrease in cells in the G1, S and G2 phases. In addition, cis-(dichloro) tetrammineruthenium(III) chloride treatment induced apoptosis in a time-dependent manner,as observed by the increased numbers of annexin V-positive cells. Taken together, these findings strongly demonstrate that DNA damage, cell cycle changes and apoptosis may correlate with the cytotoxic effects of cis-(dichloro) tetrammineruthenium (III) chloride on S-180 cells.

The compound cis-(dichloro)tetrammineruthenium(III) chloride induces caspase-mediated apoptosis in K562 cells.

Ruthenium(III) complexes are increasingly attracting the interest of researchers due to their promising pharmacological properties. In the present study, we investigated the ability of cis-(dichloro)tetrammineruthenium(III) chloride to produce lethal effects in human chronic myelogenous leukemia K562 cells. The MTT tetrazolium reduction test and the trypan blue exclusion assay revealed that the IC(50) for the compound after 48 h of incubation with K562 cells was approximately 10.74 and 73.45 microM, respectively. Interestingly, it was observed that this compound exhibits mild cytotoxicity towards MRC-5 human fibroblast cells (IC(50)>383 microM). Flow cytometric analysis revealed that cis-(dichloro)tetrammineruthenium(III) chloride was capable of change cell cycle distribution since the percentage of cells in the G1, S and G2 phases decreased. In addition, treatment with this compound induced apoptotic cell death in K562 cells, demonstrated by increased DNA content in the sub-G1-peak and a significant increase in caspase-3 activity. Assay using cyclosporin A, an inhibitor of the mitochondrial permeability transition pore (MPT) showed that the preincubation of K562 cells with this inhibitor had not effect on cis-(dichloro)tetrammineruthenium(III) chloride induced caspase-3 activation. In summary, cis-(dichloro)tetrammineruthenium(III) chloride displayed a significant cytotoxic effect through cell cycle arrest and apoptotic induction in K562 cells, which suggests that cis-(dichloro)tetrammineruthenium(III) chloride might have therapeutic potential against leukemia.

The ruthenium complex cis-(dichloro)tetraammineruthenium(III) chloride presents selective cytotoxicity against murine B cell lymphoma (A-20), murine ascitic sarcoma 180 (S-180), human breast adenocarcinoma (SK-BR-3), and human T cell leukemia (Jurkat) tumor cell lines.

The aim of present study was to verify the in vitro antitumor activity of a ruthenium complex, cis-(dichloro)tetraammineruthenium(III) chloride (cis-[RuCl(2)(NH(3))(4)]Cl) toward different tumor cell lines. The antitumor studies showed that ruthenium(III) complex presents a relevant cytotoxic activity against murine B cell lymphoma (A-20), murine ascitic sarcoma 180 (S-180), human breast adenocarcinoma (SK-BR-3), and human T cell leukemia (Jurkat) cell lines and a very low cytotoxicity toward human peripheral blood mononuclear cells. The ruthenium(III) complex decreased the fraction of tumor cells in G0/G1 and/or G2-M phases, indicating that this compound may act on resting/early entering G0/G1 cells and/or precycling G2-M cells. The cytotoxic activity of a high concentration (2 mg mL(-1)) of cis-[RuCl(2)(NH(3))(4)]Cl toward Jurkat cells correlated with an increased number of annexin V-positive cells and also the presence of DNA fragmentation, suggesting that this compound induces apoptosis in tumor cells. The development of new antineoplastic medications demands adequate knowledge in order to avoid inefficient or toxic treatments. Thus, a mechanistic understanding of how metal complexes achieve their activities is crucial to their clinical success and to the rational design of new compounds with improved potency.

The ruthenium complex cis-(Dichloro)Tetraammineruthenium(III) chloride presents immune stimulatory activity on human peripheral blood mononuclear cells.

Ruthenium compounds in general are well suited for medicinal applications. They have been investigated as immunosuppressants, nitric oxide scavengers, antimicrobial agents, and antimalarials. The aim of this study is to evaluate the immunomodulatory activity of cis-(dichloro)tetraammineruthenium(III) chloride (cis-[RuCl(2)(NH(3))(4)]Cl) on human peripheral blood mononuclear cells (PBMC). The cytotoxic studies performed here revealed that the ruthenium(III) complex presents a cytotoxic activity towards normal human PBMC, only at very high concentration. Results also showed that cis-[RuCl(2)(NH(3))(4)]Cl presents a dual role on PBMC stimulating proliferation and interleukin-2 (IL-2) production at low concentration and inducing cytotoxicity, inability to proliferate, and inhibiting IL-2 production at high concentration. The noncytotoxic activity of cis-[RuCl(2)(NH(3))(4)]Cl at low concentration towards PBMC, which correlates with the small number of annexin V positive cells and also the absence of DNA fragmentation, suggest that this compound does not induce apoptosis on PBMC. For the first time, we show that, at low concentration (10-100 microg L(-1)), the cis-[RuCl(2)(NH(3))(4)]Cl compound induces peripheral blood lymphocytes proliferation and also stimulates them to IL-2 production. These results open a new potential applicability of ruthenium(III) complexes as a possible immune regulatory compound acting as immune suppressor at high concentration and as immune stimulator at low concentration.