Ruthenium polypyridyl complexes that induce mitochondria-mediated apoptosis in cancer cells.
ABSTRACT The limitations of cisplatin-based chemotherapy, including high toxicity, undesirable side effects, and drug resistance, have motivated extensive investigations into alternative metal-based cancer therapies. Ruthenium (Ru) possesses several favorable properties suited to rational anticancer drug design and biological applications. In the present study, we synthesized a series of ruthenium polypyridyl complexes containing N,N-chelating ligands, examined their anticancer activities, and elucidated the molecular mechanisms through which they caused the cancer cell death. The results demonstrated that [Ru(phen)(2)-p-MOPIP](PF(6))(2).2H(2)O (RuPOP), a complex with potent antiproliferative activity, is able to induce mitochondria-mediated and caspase-dependent apoptosis in human cancer cells. On the basis of these results, we suggest that RuPOP may be a candidate for further evaluation as a chemopreventive and chemotherapeutic agent for human cancers, especially for melanoma.
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ABSTRACT: Over the past several decades, much attention has been focused on ruthenium complexes in antitumor therapy. Ruthenium is a transition metal that possesses several advantages for rational antitumor drug design and biological applications. In the present study, five ruthenium complexes containing amino acids were studied in vitro to determine their biological activity against sarcoma-180 tumor cells. The cytotoxicity of the complexes was evaluated by an MTT assay, and their mechanism of action was investigated. The results demonstrated that the five complexes inhibited the growth of the S180 tumor cell line, with IC50 values ranging from 22.53 µM to 50.18 µM, and showed low cytotoxicity against normal L929 fibroblast cells. Flow cytometric analysis revealed that the [Ru(gly)(bipy)(dppb)]PF6 complex (2) inhibited the growth of the tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and G0/G1 phase cell cycle arrest. Further investigation showed that complex 2 caused a loss of mitochondrial membrane potential; activated caspases 3, caspase-8, and caspase-9 and caused a change in the mRNA expression levels of caspase 3, caspase-9 as well as the bax genes. The levels of the pro-apoptotic Bcl-2 family protein Bak were increased. Thus, we demonstrated that ruthenium amino acid complexes are promising drugs against S180 tumor cells, and we recommend further investigations of their role as chemotherapeutic agents for sarcomas.PLoS ONE 01/2014; 9(10):e105865. · 3.53 Impact Factor
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ABSTRACT: The problems of acquired resistance associated with platinum drugs may be addressed by chemotherapeutics based on other transition metals as they offer the possibility of novel mechanisms of action. In this study, the cellular uptake and induction of apoptosis in A549 human non-small cell lung cancer cells of three promising osmium(ii) arene complexes containing azopyridine ligands, [Os(η(6)-arene)(p-R-phenylazopyridine)X]PF6, where arene is p-cymene or biphenyl, R is OH or NMe2, and X is Cl or I, were investigated. These complexes showed time-dependent (4-48 h) potent anticancer activity with highest potency after 24 h (IC50 values ranging from 0.1 to 3.6 μM). Cellular uptake of the three compounds as quantified by ICP-MS, was independent of their log P values (hydrophobicity). Furthermore, maximum cell uptake was observed after 24 h, with evident cell efflux of the osmium after 48 and 72 h of exposure, which correlated with the corresponding IC50 values. The most active compound , [Os(η(6)-p-cymene)(NMe2-phenylazopyridine)I]PF6, was taken up by lung cancer cells predominately in a temperature-dependent manner indicating that energy-dependent mechanisms are important in the uptake of . Cell fractionation studies showed that all three compounds accumulated mainly in cellular membranes. Furthermore, compound induced apoptosis and caused accumulation in the S-phase of the cell cycle. In addition, induced cytochrome c release and alterations in mitochondrial membrane potential even after short exposure times, indicating that mitochondrial apoptotic pathways are involved. This study represents the first steps towards understanding the mode of action of this promising class of new osmium-based chemotherapeutics.Metallomics 03/2014; · 4.10 Impact Factor
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ABSTRACT: We report the synthesis and characterization of eight half-sandwich cyclopentadienyl Ir(III) pyridine complexes of the type [(η(5)-Cp(xph))Ir(phpy)Z]PF6, in which Cp(xph) = C5Me4C6H5 (tetramethyl(phenyl)cyclopentadienyl), phpy = 2-phenylpyridine as C(∧)N-chelating ligand, and Z = pyridine (py) or a pyridine derivative. Three X-ray crystal structures have been determined. The monodentate py ligands blocked hydrolysis; however, antiproliferative studies showed that all the Ir compounds are highly active toward A2780, A549, and MCF-7 human cancer cells. In general the introduction of an electron-donating group (e.g., Me, NMe2) at specific positions on the pyridine ring resulted in increased antiproliferative activity, whereas electron-withdrawing groups (e.g., COMe, COOMe, CONEt2) decreased anticancer activity. Complex 5 displayed the highest anticancer activity, exhibiting submicromolar potency toward a range of cancer cell lines in the National Cancer Institute NCI-60 screen, ca. 5 times more potent than the clinical platinum(II) drug cisplatin. DNA binding appears not to be the major mechanism of action. Although complexes [(η(5)-Cp(xph))Ir(phpy)(py)](+) (1) and [(η(5)-Cp(xph))Ir(phpy)(4-NMe2-py)](+) (5) did not cause cell apoptosis or cell cycle arrest after 24 h drug exposure in A2780 human ovarian cancer cells at IC50 concentrations, they increased the level of reactive oxygen species (ROS) dramatically and led to a loss of mitochondrial membrane potential (ΔΨm), which appears to contribute to the anticancer activity. This class of organometallic Ir complexes has unusual features worthy of further exploration in the design of novel anticancer drugs.Organometallics 10/2014; · 4.15 Impact Factor