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PubMed2002

Inhibition of endothelial cell functions and of angiogenesis by the metastasis inhibitor NAMI-A.

NAMI-A is a ruthenium-based compound with selective anti-metastasis activity in experimental models of solid tumours. We studied whether this activity was dependent on anti-angiogenic ability of NAMI-A. We thus investigated its in vitro effects on endothelial cell functions necessary for angiogenesis to develop, as well as its in vivo effects in the chick embryo chorioallantoic membrane model. Endothelial cell proliferation, chemotaxis, and secretion of the matrix-degrading enzyme metalloproteinase-2 were inhibited by NAMI-A in a dose-dependent manner, and without morphologic signs of cell apoptosis or necrosis. Lastly, NAMI-A displayed a dose-dependent in vivo anti-angiogenic activity in the chorioallantoic membrane model. These data suggest that the anti-angiogenic activity of NAMI-A can contribute to its anti-metastatic efficacy in mice bearing malignant solid tumours.

Angiogenesis Inhibitors↗
PubMed2004

Intratumoral NAMI-A treatment triggers metastasis reduction, which correlates to CD44 regulation and tumor infiltrating lymphocyte recruitment.

Intratumor (i.t.) injection of 35 mg/kg/day NAMI-A for six consecutive days to CBA mice bearing i.m. implants of MCa mammary carcinoma reduces primary tumor growth and particularly lung metastasis formation, causing 60% of animals to be free of macroscopically detectable metastases. The i.t. treatment allows study of the effects of NAMI-A on in vivo tumor cells exposed to millimolar concentrations for a relatively prolonged time. Under these conditions, NAMI-A reduces the number of CD44+ tumor cells and changes tumor cell phenotype to a lower aggressive behavior, as shown by scanning electron microscopy analysis. On primary tumor site, NAMI-A causes unbalance between 2n and aneuploid cells in favor of lymphocytes. Furthermore, in tumor tissue, nitric oxide production is increased and active matrix metalloproteinase 9 is decreased, and these effects are accompanied by a reduced hemoglobin concentration. These data are in agreement with the reduction of tumor invasion and metastasis and suggest the therapeutic usefulness of NAMI-A in neoadjuvant or tumor reduction treatments for preventing metastasis formation. These data further stress the usefulness of intratumor treatments as experimental preclinical model for studying in vivo the mechanism of tumor cell interactions after prolonged exposure to ruthenium-based compounds to be developed for metastasis inhibition.

Animals↗
PubMed2005

Ruthenium (II)-derived organometallic compounds induce cytostatic and cytotoxic effects on mammalian cancer cell lines through p53-dependent and p53-independent mechanisms.

The metallic compound cisplatin has been used for many years to treat various human cancers. Here, we describe the cytostatic and cytotoxic properties of a new class of organometallic compounds that contain a ruthenium (II) atom covalently linked to carbon and nitrogen atoms. We found that several ruthenium-derived compounds (RDCs) led to G1 arrest and induced apoptosis in tumor cell lines derived from glioblastomas, neuroblastomas, and lymphoid tumors at least as efficiently as cisplatin. We further analyzed the signaling pathways underlying these effects, and we showed that both RDCs and cisplatin induced p53 and p73 protein levels but with different intensities and kinetics. This accumulation of p53 and p73 proteins correlated with an increase in p21 and Bax expression, two p53 target genes linked to cell growth arrest and apoptosis. However, in contrast to cisplatin-induced apoptosis, overexpression of DeltaNp73, a p53 and p73 dominant-negative isoform, only partly reduced RDC-induced apoptosis, suggesting p53-dependent and p53-independent modes of action. This observation was further confirmed by the ability of RDC to induce apoptosis in p53-/- cells. Altogether, this study highlights key cellular and molecular features of RDCs and suggests that further development of this new class of compounds may contribute to improve future chemotherapeutic protocols.

Animals↗
PubMed1991

New platinum, titanium, and ruthenium complexes with different patterns of DNA damage in rat ovarian tumor cells.

DNA protein cross-links (DPC), DNA interstrand cross-links (ISCL), and DNA single strand breaks following treatment of experimental ovarian tumor cells (O-342) with five new metal complexes (three platinum, one titanium, one ruthenium compounds) were investigated at 6, 24, and 48 h after drug exposure and compared with their in vitro growth inhibitory potential. cis-Diamminedichloroplatinum(II) (cisplatin, DDP) served as reference drug. The following new compounds were tested: 18-crown-6-tetracarboxybis-diammineplatinum(II) (CTDP), cis-aminotrismethylenephosphonato-diammineplatinum(II) (AMDP), cis-diamminecyclohexano-aminotrismethylenephosphonato-platin um(II) (DAMP), diethoxybis-(1-phenylbutane-1,3-dionato)-titanium(IV) (budotitane), and trans-indazolium-tetrachlorobisindazole-ruthenate(III) (IndCR). At equimolar concentrations DNA cross-linking activity of the platinum agents decreased in the order cisplatin, CTDP, AMDP, DAMP; this was paralleled by growth inhibition in a cell proliferation assay. CTDP-induced interstrand cross-linking occurred more slowly compared to cisplatin (DDP) (6 h: CTDP, 73 +/- 15 versus DDP, 365 +/- 72 rad equivalents), but reached a peak similar to cisplatin 24 h after exposure (CTDP, 317 +/- 68 versus DDP, 392 +/- 116 rad equivalents). At this time point in contrast to DDP no DNA protein cross-links were observed for CTDP (total cross-links: CTDP 310 +/- 71, DDP 1987 +/- 436 rad equivalents). Thus, at 24 h, CTDP was found to be distinctly less reactive to proteins than DDP, and it is suggested that CTDP might be similar in its toxicity pattern to the structurally related compound carboplatin which was also reported to be less reactive to protein than DDP. By 48 h, CTDP- and DDP-induced interstrand cross-links were 65 +/- 21 and 180 +/- 33 rad equivalents, respectively. Although at a lower level, by 24 h, AMDP showed a ratio of ISCL to total cross-links (179 +/- 39 versus 213 +/- 31 rad equivalents), which was comparable to CTDP. The second biphosphonate complex DAMP was the least active platinum compound in terms of DNA damage, effecting only 16 +/- 7 rad equivalents ISCL and 63 +/- 28 rad equivalents total cross-links; similar to DDP, DAMP displayed a higher DPC fraction at 24 h. The titanium complex diethoxybis-(1-phenylbutane-1,3-dionato)-tita-++ +nium(IV) showed dose-dependent inhibition of cell proliferation, while no significant DNA damage could be detected with the alkaline elution technique. These results, together with observations from other authors, indicating that space-filling planar aromatic ring systems are important for its antitumor activity, suggest as possible mechanism of action of diethoxybis-(1-phenylbutane-1,3-dionato)-titanium(IV) intercalation into the DNA.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

Photoelectrochemical oxidation of DNA by ruthenium tris(bipyridine) on a tin oxide nanoparticle electrode.

Selective photoelectrochemical oxidation of DNA was achieved by ruthenium tris(bipyridine) immobilized on a tin oxide nanoparticle electrode. The metal complex was covalently attached to a protein, avidin, which adsorbed strongly on the tin oxide electrode by electrostatic interaction. Upon irradiation with 473-nm light, anodic photocurrent was generated in a blank electrolyte and was enhanced significantly after addition of poly(guanadylic acid) (poly-G) into the electrolyte. The current increased progressively with the nucleotide concentration, suggesting the enhancement effect was related to poly-G. The action spectrum indicates that the photocurrent was initiated by light absorption of the ruthenium compound immobilized on the electrode. Among the various polynucleotides examined, poly-G produced the largest photocurrent increase, followed by poly-A, single-stranded DNA, chemically damaged DNA, and double-stranded DNA, whereas poly-C and poly-U showed little effect. The combined experimental data support the hypothesis that the photoexcited Ru2+ species injects an electron into the semiconductor and produces Ru3+, which is then reduced back to Ru2+ by guanine and adenine bases in DNA, resulting in the recycling of the metal complex and enhanced photocurrent. The photoelectrochemical reaction can be employed as a new method for the detection of DNA damage.

2,2'-Dipyridyl↗
PubMed1986

Effect of compound 48/80 and ruthenium red on the Ca2+-ATPase of sarcoplasmic reticulum.

The effects of the condensation product of N-methyl-p-methoxyphenethylamine with formaldehyde (compound 48/80) and ruthenium red on the partial reactions of the catalytic cycle of the sarcoplasmic reticulum Ca2+-ATPase of skeletal muscle were studied. The ATPase activity and both Ca2+ and Sr2+ uptake were inhibited by compound 48/80 when oxalate was used as a precipitating agent. The degree of inhibition decreased when oxalate was replaced by orthophosphate as the precipitating anion. Both the fast Ca2+ efflux and the synthesis of ATP observed during reversal of the Ca2+ pump were inhibited by compound 48/80. Inhibition of the reversal of the Ca2+ pump was caused by a competition between compound 48/80 and orthophosphate for the phosphorylation site of the enzyme. The fast Ca2+ release promoted by arsenate was impaired by compound 48/80. Ruthenium red competes with Ca2+ for the high affinity binding site of the Ca2+-ATPase, but did not interfere with the binding of Ca2+ to the low affinity binding site of the enzyme. In presence of Ca2+ concentrations higher than 5 microM, ruthenium red in concentrations up to 200 microM had no effect on both ATPase activity and Ca2+ uptake. However, the fast Ca2+ efflux promoted by arsenate and the fast Ca2+ efflux coupled with the synthesis of ATP observed during the reversal of the Ca2+ pump were inhibited by ruthenium red, half-maximal inhibition being attained in presence of 10-20 microM ruthenium red. In contrast to the effect of compound 48/80, ruthenium red did not inhibit the phosphorylation of the enzyme by orthophosphate. The ATP in equilibrium with Pi exchange catalyzed by the Ca2+-ATPase in the absence of transmembrane Ca2+ gradient was also inhibited by ruthenium red.

Adenosine Triphosphate↗
PubMedDate not supplied

[Development of a novel enzyme-redox-mediator system based on a fungal laccase and ruthenium complexes].

The laccase produced by the fungus Coriolus hirsutus has been coordinatively modified with ruthenium complexes [Ru(phpy)(phen)(MeCN)2]PF6 and Ru(bpy)2CO3 under aerobic and anaerobic conditions. The amount of the complexes per enzyme molecule does not depend on the oxygen concentration, equaling 5 for [Ru(phpy)(phen)(MeCN)2]PF6 and 3 for Ru(bpy)2CO3. The pH dependence of the enzymatic activity, thermostability, and catalytical and electrocatalytical properties of the modified laccase are reported. It has been shown that, during the modification, at least one molecule of the ruthenium compound was coordinated near the T1 active center of the laccase, being directly involved in the catalysis and enhancing its efficiency.

2,2'-Dipyridyl↗
PubMedDate not supplied

Drug control of solid tumour metastases: a critical view.

Metastasis of solid tumours represent the target of election for the pharmacological treatment of cancer. Nevertheless, commonly used treatments do not represent any selective approach, provided that drugs are mostly unspecific cytotoxics. Today many strategies adopted to interfere with metastasis growth concern the interaction with biological signals of the metastatic cells or of the host. One difference should be made between anti-metastatic and anti-metastasis drugs, in that only the latter realise the goal of selectively destroying metastasis wherever they are. In this context many agents active on newly identified molecular targets are more effective in preventing metastasis formation than in inhibiting their growth. NAMI-A, an innovative ruthenium compound, seems to provide optimism for the future and, in laboratory models, it is very active on lung metastases independently of the stage of their growth. The success of NAMI-A against metastasis should stimulate laboratory studies with appropriate experimental models to predict clinical activity, since the use of experimental conditions closely similar to those of human tumours should help the identification of more active compounds.

Animals↗
PubMed2001

Biophysical analysis of natural, double-helical DNA modified by anticancer heterocyclic complexes of ruthenium(III) in cell-free media.

Modifications of natural DNA by three anticancer heterocyclic ruthenium(III) compounds were studied by methods of molecular biophysics. These methods included DNA binding studies using atomic absorption spectrophotometry, inhibition of restriction endonucleases, mapping of DNA adducts by transcription assay, interstrand cross-linking employing gel electrophoresis under denaturing conditions, DNA unwinding studied by gel electrophoresis, circular dichroism analysis of the B-->Z transition in DNA, and DNA melting curves measured by absorption spectrophotometry. The results indicate that the complexes HIm[trans-Cl4Im2RuIII], HInd[trans-Cl4Ind2RuIII], and Na[trans-Cl4Im(Me2SO)RuIII] (Im and Ind stand for imidazole and indazole, respectively) coordinate irreversibly to DNA. Their DNA binding mode is, however, different from that of cisplatin. Interestingly, Na[trans-Cl4Im(Me2SO)RuIII] binds to DNA considerably faster than the other two ruthenium compounds and cisplatin. In addition, when Na[trans-Cl4Im(Me2SO)RuIII] binds to DNA it exhibits an enhanced base sequence specificity in comparison with the other two ruthenium complexes. Na[trans-Cl4Im(Me2SO)RuIII] also forms bifunctional intrastrand adducts on double-helical DNA which are capable of terminating RNA synthesis in vitro, while the capability of the other two ruthenium compounds to form such adducts is markedly lower. This observation has been interpreted to mean that the bifunctional adducts of HInd[trans-Cl4Ind2RuIII] and Na[trans-Cl4Im2RuIII] formed on rigid double-helical DNA are sterically more crowded by their octahedral geometry than those of Na[trans-Cl4Im(Me2SO)RuIII]. In addition, the adducts of all three ruthenium compounds affect the conformation of DNA, Na[trans-Cl4Im(Me2SO)RuIII] being most effective. It has been suggested that the altered DNA binding mode of ruthenium compounds in comparison with cisplatin might be an important factor responsible for the altered cytostatic activity of this class of ruthenium compounds in tumor cells.

Antineoplastic Agents↗
PubMed2006

Organometallic compounds with biological activity: a very selective and highly potent cellular inhibitor for glycogen synthase kinase 3.

A chiral second-generation organoruthenium half-sandwich compound is disclosed that shows a remarkable selectivity and cellular potency for the inhibition of glycogen synthase kinase 3 (GSK-3). The selectivity was evaluated against a panel of 57 protein kinases, in which no other kinase was inhibited to the same extent, with a selectivity window of at least tenfold to more than 1000-fold at 100 microM ATP. Furthermore, a comparison with organic GSK-3 inhibitors demonstrated the superior cellular activity of this ruthenium compound: wnt signaling was fully induced at concentrations down to 30 nM. For comparison, the well-established organic GSK-3 inhibitors 6-bromoindirubin-3'-oxime (BIO) and kenpaullone activate the wnt pathway at concentrations that are higher by around 30-fold and 100-fold, respectively. The treatment of zebrafish embryos with the organometallic inhibitor resulted in a phenotype that is typical for the inhibition of GSK-3. No phenotypic change was observed with the mirror-imaged ruthenium complex. The latter does not, in fact, show any of the pharmacological properties for the inhibition of GSK-3. Overall, these results demonstrate the potential usefulness of organometallic compounds as molecular probes in cultured cells and whole organisms.

Animals↗
PubMed2004

Different subunit location of the inhibition and transport sites in the mitochondrial calcium uniporter.

The mitochondrial calcium uniporter behaves as a cooperative mechanism, where the velocity is dependent on [Ca2+]ex. Transport kinetics follows a sigmoidal behavior with a Hill coefficient near 2.0, indicating the binding of at least two calcium molecules. Calcium transport in mitochondria is dependent on a negative inner membrane potential and is inhibited by policationic ruthenium compounds. In this study, calcium uptake activity was reconstituted into cytochrome oxidase vesicles by incorporating solubilized mitochondrial proteins. Calcium accumulation plotted against increasing Ca2+ concentrations followed a sigmoidal behavior with a Hill coefficient of 1.53. The uptake was sensitive to ruthenium policationic inhibitors, e.g. ruthenium red and Ru360. After mitochondrial proteins were separated by preparative isoelectrofocusing and incorporated into cytochrome oxidase vesicles, two peaks of calcium uptake activity were recovered. One of the activities was inhibited by Ru360, while the second activity was insensitive to Ru360 and was associated with proteins focused at very acidic isoelectric points. By using a thiol-group crosslinker and radiolabeled Ru360, we proposed a scheme of partial dissociation of the uniporter inhibitor-binding subunit under acidic conditions.

Animals↗
PubMed2003

Electroluminescent device with reversible switching between red and green emission.

Research on new materials for organic electroluminescence has recently focused strongly on phosphorescent emitters, with the aim of increasing the emission efficiency and stability. Here we report the fabrication of a simple electroluminescent device, based on a semiconducting polymer combined with a phosphorescent complex, that shows fully reversible voltage-dependent switching between green and red light emission. The active material is made of a polyphenylenevinylene (PPV) derivative molecularly doped with a homogeneously dispersed dinuclear ruthenium complex, which fulfils the dual roles of triplet emitter and electron transfer mediator. At forward bias (+4 V), the excited state of the ruthenium compound is populated, and the characteristic red emission of the complex is observed. On reversing the bias (-4 V), the lowest excited singlet state of the polymer host is populated, with subsequent emission of green light. The mechanism for the formation of the excited state of the PPV derivative involves the ruthenium dinuclear complex in a stepwise electron transfer process that finally leads to efficient charge recombination reaction on the polymer.

Journal Article↗
PubMed2001

A new polytopic bis-diazacrown-ether-polypyridine ligand and its complexes with Zn(II) salts and mononuclear and dendritic Ru(II) precursors. Synthesis, absorption spectra, redox behavior, and luminescence properties.

The new polytopic receptor 1 containing two terpyridine, one phenanthroline, and two diazacrown-ether sites has been prepared using a modular approach. Such a new species contains several pieces of information in its structure which can be processed by different metal ions to give different supramolecular inorganic architectures. Actually, reaction of 1 with Zn(CH(3)COO)(2) in methanol, and subsequent anion exchange, afforded the intramolecular ring-type [Zn(1)](2+) complex, which appears to be formed by a self-assembling reaction. A different synthetic approach, stepwise synthesis, allowed us to synthesize the two multicomponent compounds [(bpy)(2)Ru(mu-1)Ru(bpy)(2)](4+) (Ru2; bpy = 2,2'-bipyridine) and [[(bpy)(2)Ru(mu-2,3-dpp)](2)Ru(mu-1)Ru[(mu-2,3-dpp)Ru(bpy)(2)](2)](12+) (Ru6; 2,3-dpp = 2,3-bis(2-pyridyl)pyrazine). The absorption spectra and luminescence properties of 1 and [Zn(1)](2+) are dominated by pi --> pi transitions and excited states. The absorption spectra of the ruthenium compounds are dominated by ligand-centered (LC) bands in the UV region and metal-to-ligand charge-transfer (MLCT) bands in the visible. The latter compounds undergo several reversible metal-centered oxidations and ligand-centered reductions in the potential window investigated (-2.0/+2.0 V versus SCE) and exhibit MLCT luminescence in both acetonitrile fluid solution at room temperature and in butyronitrile rigid matrix at 77 K. Both the redox and photophysical properties of Ru2 and Ru6 can be assigned to specific subunits of the multicomponent structures. The data indicate that the [Ru(bpy)(2)](2+) and the dendritic [Ru[(mu-2,3-dpp)Ru(bpy)(2)](2)](6+) fragments appended to the polytopic 1ligands behave as independent components of the multicomponent arrays.

Journal Article↗
PubMed1991

Calcium chelation induced glutathione efflux from tumor cells and prevention by ruthenium red or neomycin.

Cultured human lung carcinoma cells (A549) were incubated in a calcium-free medium containing calcium chelators (EGTA, 1-10 mM or BAPTA, 5 mM) for 1 hour at 37 degrees C. With limited toxicity, the presence of calcium chelators resulted in a decrease of cellular GSH and detachment of the cells from the tissue culture flask. The permeable EGTA tetraacetoxymethyl ester (0.5mM-5 mM) caused a decrease in the cellular GSH content without cell detachment. GSH was not oxidized to GSSG nor formed mixed disulfides with protein thiols. AT-125, a gamma-glutamyl transpeptidase inhibitor, prevented detachment, but not the efflux of cellular GSH. Pretreatment with two impermeable compounds (ruthenium red, 100 microM and neomycin, 0.5-10 mM) protected the cells from detachment and prevented the decrease in intracellular GSH. The presence of calcium in the medium during the EGTA and BAPTA treatments also protected the cells. Calcium associated with the cytoplasmic membrane phospholipids or proteins appears important to limit membrane permeability for GSH efflux and to maintain cell attachment.

Calcium↗
PubMed2007

Oxidation of linear trinuclear ruthenium complexes [Ru(3)(dpa)(4)Cl(2)] and [Ru(3)(dpa)(4)(CN)(2)]: synthesis, structures, electrochemical and magnetic properties.

The neutral, monocationic, and dicationic linear trinuclear ruthenium compounds [Ru(3)(dpa)(4)(CN)(2)], [Ru(3)(dpa)(4)(CN)(2)][BF(4)], [Ru(3)(dpa)(4)Cl(2)][BF(4)], and [Ru(3)(dpa)(4)Cl(2)][BF(4)](2) (dpa=the anion of dipyridylamine) have been synthesized and characterized by various spectroscopic techniques. Cyclic voltammetric and spectroelectrochemical studies on the neutral and oxidized compounds are reported. These compounds undergo three successive metal-centered one-electron-transfer processes. X-ray structural studies reveal a symmetrical Ru(3) unit for these compounds. While the metal--metal bond lengths change only slightly, the metal--axial ligand lengths exhibit a significant decrease upon oxidation of the neutral complex. The electronic configuration of the Ru(3) unit changes as the axial chloride ligands are replaced by the stronger "pi-acid" cyanide axial ligands. Magnetic measurements and (1)H NMR spectra indicate that [Ru(3)(dpa)(4)Cl(2)] and [Ru(3)(dpa)(4)Cl(2)][BF(4)](2) are in a spin state of S=0 and [Ru(3)(dpa)(4)Cl(2)][BF(4)], [Ru(3)(dpa)(4)(CN)(2)], and [Ru(3)(dpa)(4)(CN)(2)][BF(4)] are in spin states of S=1/2, 1, and 3/2, respectively. These results are consistent with molecular orbital (MO) calculations.

Journal Article↗
PubMed1990

Cytochemical evidence for a proteoglycan-associated filamentous network in ligament extracellular matrix.

The purpose of this investigation was to examine the extracellular matrix of rabbit ligament before and after digestion with glycosaminoglycan degrading enzymes. In order to preserve and enhance the visibility of negatively charged tissue components, particularly the glycosaminoglycan-containing proteoglycans, the cationic stains ruthenium red (RR) and ruthenium hexamine trichloride (RHT) were used. Cross-sections of the midsubstance of 10-month-old (mature) rabbit medial collateral ligaments fixed using conventional procedures revealed a sparse population of stellate-shaped cells that did not appear to be interconnected. Similar tissue fixed in either RR or RHT showed an extensive network of thin, electron-dense "seams" that interconnected cells and appeared to irregularly subdivide the extracellular matrix (ECM). These seams mainly consisted of a meshwork of microfilaments throughout which small granules were dispersed. Numerous 14-nm microfibrils, as well as mature elastic fibers were also present within the seams. The size and shape of the microfilaments, together with their threadlike, beaded appearance suggested that they could be Type VI collagen. The seam granules were easily removed with chondroitinase ABC, chondroitinase AC II, and mild (0.18 M) salt treatment. Only chondroitinase ABC succeeded in removing additional granules, tentatively identified as proteodermatan sulphate molecules, that were periodically located at d band sites along the Type I collagen fibrils. These results suggest that the seam granules are not dermatan sulphate containing proteoglycans, and further, that these proteoglycans may be sequestered into specific zones within the ECM through loose association with the seam microfilaments. While the functional significance of the seams remains unknown and their specific composition clearly requires further study, it is likely that they represent important functional (e.g., viscoelastic) or biological (e.g., nutritional) subdivisions of ligament substance.

Animals↗
PubMed2003

In vitro immunomodulatory activity of ruthenium complexes.

OBJECTIVE AND DESIGN: We have explored the in vitro immunomodulatory effects of pure ruthenium red and a series of pyridine and imidazole substituted ruthenium complexes (RCs). MATERIAL: Human peripheral blood lymphocytes and purified T cells were used in these studies along with various cell lines. METHODS: Cells were treated with dilutions of RCs and assessed in various assays of immune function, cytotoxicity and cell cycle progression. RESULTS: RCs efficiently blocked T cell receptor (TCR)-mediated stimulation (IC(50)'s in the low nM range) of human peripheral blood lymphocytes (hPBL) by various agents, including tetanus toxoid, alloantigens, superantigens, and receptor-specific antibodies. RCs are not cytotoxic to T cells. Antiproliferative activity was also observed for B cells. Some non-lymphoid cell lines or primary cultures showed sensitivity to the RCs, but only at higher concentrations. The inhibitory effect on human T cells was assessed and demonstrated at the level of proliferation (DNA synthesis), IL-2 secretion, and IL-2 receptor (CD25) upregulation. RCs also inhibited IL-2-mediated proliferation of antigen-induced T-cell blasts and the IL-2-dependent T cell line Kit-225. Cell cycle analysis indicates that RCs inhibit the progression of activated T cells from G(0)/G(1) to S phase. CONCLUSIONS: Since the mechanism of T cell inhibition by RCs appears to be different than that of rapamycin (RAP) or cyclosporin A (CsA), they may provide a new tool to investigate intracellular signaling in T cells, and may present novel opportunities for immunosuppression

Animals↗
PubMed2004

Cocultures of metastatic and host immune cells: selective effects of NAMI-A for tumor cells.

The effects of NAMI-A, [H2im][trans-RuCl4(dmso-S)(Him)], a new metal-based agent for treating tumor metastases, have been investigated in vitro on splenocytes, ConA- or LPS-activated T and B lymphoblasts, and thymocytes. Splenocytes and thymocytes exposed for 1 h to 0.01-0.1-mM NAMI-A do not change their mitochondrial functionality, cell cycle distribution, protein synthesis, and CD44 expression in comparison to untreated control samples. Instead, mitochondrial functionality increased 24 h after treatment in a fraction of splenocytes. The same treatment reduced mitochondrial functionality and S phase of the cell cycle in T and B blasts (already after 1 h treatment) and reduced CD44 expression on B blasts, 24 h after treatment. On cocultures of splenocytes and metastatic cells (metGM) (1:1), NAMI-A induces a selective depolarization of mitochondrial membrane potential of metGM cells, while it stimulates splenocytes (mainly lymphocytes), as shown by the increase of the S phase, nitric oxide production, and adhesion onto metastatic cells. This, in turn, reduces the number of metastatic cells and results in the increased ratio between splenocytes and metGM in favor of diploid cells (doubling from one to two). Rosetting of leukocytes onto metastatic cells correlates with induction of CD54 expression on tumor cells after NAMI-A in vivo treatment, which in turn, might contribute to metastasis recognition by cytotoxic lymphocytes. The overall antimetastatic activity displayed by NAMI-A might therefore be the result of complex interactions with tumor cells, on which it displays selective antitumor activity, and with host immune cells through which it promotes activation of host immune defenses involved in tumor suppression.

Animals↗