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Background:Platinum-based drugs such as Cisplatin are commonly employed for cancer treatment. Despite an initial therapeutic response, Cisplatin treatment often results in the development of chemoresistance. To identify novel approaches to overcome Cisplatin resistance, we tested Cisplatin in combination with K + channel modulators on colorectal cancer (CRC) cells.Methods:The functional expression of Ca 2+ -activated (K Ca 3.1, also known as KCNN4) and voltage-dependent (K v 11.1, also known as KCNH2 or hERG1) K + channels was determined in two CRC cell lines (HCT-116 and HCT-8) by molecular and electrophysiological techniques. Cisplatin and several K + channel modulators were tested in vitro for their action on K + currents, cell vitality, apoptosis, cell cycle, proliferation, intracellular signalling and Platinum uptake. These effects were also analysed in a mouse model mimicking Cisplatin resistance.Results:Cisplatin-resistant CRC cells expressed higher levels of K Ca 3.1 and K v 11.1 channels, compared with Cisplatin-sensitive CRC cells. In resistant cells, K Ca 3.1 activators (SKA-31) and K v 11.1 inhibitors (E4031) had a synergistic action with Cisplatin in triggering apoptosis and inhibiting proliferation. The effect was maximal when K Ca 3.1 activation and K v 11.1 inhibition were combined. In fact, similar results were produced by Riluzole, which is able to both activate K Ca 3.1 and inhibit K v 11.1. Cisplatin uptake into resistant cells depended on K Ca 3.1 channel activity, as it was potentiated by K Ca 3.1 activators. K v 11.1 blockade led to increased K Ca 3.1 expression and thereby stimulated Cisplatin uptake. Finally, the combined administration of a K Ca 3.1 activator and a K v 11.1 inhibitor also overcame Cisplatin resistance in vivo.Conclusions:As Riluzole, an activator of K Ca 3.1 and inhibitor of K v 11.1 channels, is in clinical use, our results suggest that this compound may be useful in the clinic to improve Cisplatin efficacy and overcome Cisplatin resistance in CRC.

In the present study, the interactions between cisplatin and cytochrome c are investigated. Based on high-resolution X-ray diffraction data, two monometalated species, i.e. cyt c-Pt(NH3)2 and cyt c-Pt(NH3)2Cl, are found to be the main adducts that form in the reaction between the protein and the drug. Both monodentate and bidentate platinum coordination to the protein is observed, with platinum binding either to Met65 or to Met65 and Glu61, simultaneously.

Gold is a nonessential element with a variety of applications in medicine. A few gold(I) compounds are used in the clinics for treatment of rheumatoid arthritis and of discoid lupus. Some novel gold(III) compounds are under evaluation as anticancer agents. It is known that gold compounds generally produce toxic effects on the kidneys and characteristic lesions in the brain. However, information concerning the neurotoxicity of gold derivatives in humans as well as in experimental toxicology is rather scarce. For this reason we tried to shed some further light on this aspect of gold neurotoxicity by chronic treatment of mice with sodium tetrachloroaurate(III) in order to observe possible biophysical and morphological alterations that may occur in the brain. Chronic gold treatment resulted in a markedly decreased expression of metallothioneins and of glial fibrillary acidic protein in astrocytes of different brain areas. To examine its effects on cell membranes, interactions of sodium tetrachloroaurate(III) with molecular models were also evaluated. The models consisted in bilayers built-up of classes of phospholipids located in the outer and inner monolayers of biological membranes. Structural perturbation of cell membrane models was observed only at concentrations 10(5) times higher than those detected in the brains of animals after three months' treatment. These results show that toxic effects on animal brain upon treatment with sodium tetrachloroaurate develop with difficulty and may be observed only at high doses.

The interaction of two antitumor ruthenium(III) complexes,-Na[trans-RuCl(4)(DMSO)(Im)] and Na[trans-RuCl(4)(DMSO)(Ind)]- with human serum apotransferrin (apoTf) was investigated through a number of spectroscopic techniques such as UV-Vis absorption, CD and (1)H NMR spectroscopy. Interestingly, the hydrolysis profiles of these complexes in a physiological buffer are markedly affected by the presence, in solution, of apoTf suggesting the occurrence of a specific interaction of their respective hydrolysis products with the protein. The formation of stable adducts with apotransferrin has been demonstrated by CD spectroscopy, and additional information obtained through (1)H NMR of the hyperfine shifted signals. The bound ruthenium(III) species may be detached from these adducts by addition of excess citrate at low pH. The behavior of the investigated ruthenium(III) complexes with apoTf is compared with that of the recently described and strictly related ru-im and ru-ind antitumour complexes, and discussed in the frame of general strategies of drug targeting.

From the polar extracts of the leaves of Quercus ilex L., two new proanthocyanidin glycosides, namely afzelechin-(4α→8)-catechin-3-O-β-glucopyranoside (1) and afzelechin-(4α→8)-catechin-3-O-α-rhamnopyranoside (2), were isolated in addition to catechin (3), proanthocyanidin B3 (4), prodelphinidin C (5), dehydrodicatechin A (6), quercetin (7) and six known flavonol glucosides with their acylated derivatives (8-13) and ellagic acid (14). The structures of all isolated compounds were established by spectroscopic means, mainly 1D and 2D NMR, as well as LC/MS and HR-MS spectrometric analyses. The absolute configuration of compound 1 was determined by CD measurements. The proanthocyanidin glycosides are especially interesting, as they possess the sugar in the upper unit of the dimer, which is rare for this type of compounds. © 2009 Elsevier Ltd. All rights reserved.

A variegate group of metallodrugs was evaluated in vitro for antimalarial activity through the pLDH test. The panel comprised one mononuclear gold(III) complex, (Aubipy), three dinuclear gold(III) compounds (Auoxo4, Auoxo5 and Auoxo6), three ruthenium(III) complexes (NAMI A, PMRU20, PMRU27), one ruthenium(II) complex (PMRU52), one bismuth(III) compound (Bismuth citrate), antimony trichloride (SbCl3) and arsenic trioxide (As2O3). This panel, although relatively small, was built up in such a way to include a variety of metal centers, structural motifs and metal coordination environments. In general, the tested compounds turned out to contrast effectively Plasmodium falciparum growth in vitro. In two cases, i.e. NAMI A and antimony trichloride, IC50 values in the high nanomolar range were measured. Notably, the antiplasmodial effects appear not to be correlated to in vitro anticancer properties. The mechanistic and pharmacological implications of the obtained results are discussed.

The reaction of [Ru2(CO)6Cl4], 1, with excess THZ (1,3-thiazole) in absolute ethanol at 55 degrees C produces fac-[Ru(CO)3Cl2(THZ)], 2, in high yield. [Ru(CO)2Cl2(THZ)2], 3, is formed at higher temperature (ca 70 degrees C) and higher concentration of THZ. The X-ray structures of the new compounds have been determined, and density functional studies performed at the hybrid B3LYP/(Lanl2DZ, Ru; 6-311+G**, CHClNOS) level allowed the estimation of the structures of several conformers as well as that of their relative total electronic energies. Compound 2 is soluble (slowly) in aqueous media, where it reacts with the transport proteins bovine serum albumin (BSA) and human apotransferrin (HTF), and at a lower extent with calf thymus DNA (CT-DNA) and with guanosine-5'-monophosphate (GMP). The complex molecule is adsorbed by certain synthetic acryloyl polymers that have terminal carboxylate functions and is embedded in silica gels when these latter are prepared in the presence of a solution of 2. Ruthenium species are slowly released from the loaded gels into physiological solutions at pH 7.4. The reactivity of 2 with biomolecules and synthetic hydrogels makes it a compound of interest for anticancer and antimetastases tests.